Use of Exogenous Enzymes in Human Therapy: Approved Drugs and
Potential Applications

doi:10.2174/0929867328666210713094722
摘要

在过去的几十年中，安全有效的基于酶的人类疗法的发展大大增加，这要归功于对导致不同疾病的分子机制的理解的显着进步，以及可能在治疗此类病理中起到补救作用的相关外源酶的催化活性的表征。几种基于酶的生物治疗药物已获得FDA（美国食品和药物管理局）和EMA（欧洲药品管理局）的批准，许多正在进行临床试验。除了本综述中未讨论的人类遗传疾病中的酶替代疗法外，已批准的用于人类治疗的酶在几个领域都有应用，从癌症治疗到溶栓以及凝血障碍，囊性纤维化，乳糖不耐症和基于胶原蛋白的疾病的治疗。大多数治疗酶来自微生物，由于快速，简单和具有成本效益的生产和操作，这是最方便的来源。微生物重组酶的使用拓宽了人类治疗的前景，但仍需要解决一些障碍，例如高免疫原性，蛋白质不稳定性，短半衰期和低底物亲和力。酶的替代来源，副作用减少，活性提高，以及酶的遗传修饰和新型递送系统不断被搜索。化学修饰策略，靶向和/或纳米载体介导的递送，定向进化和位点特异性诱变，遗传操作产生的融合蛋白是降低毒性和提高生物利用度和细胞靶向的最探索的工具。该评价描述了目前用于人类疾病治疗管理的外源性酶，其当前FDA / EMA批准状态，以及已经在临床水平上进行实验和潜在有希望的候选者。
关键词: 重组蛋白，药物酶，抗癌生物制剂，纤维蛋白溶解疗法，癌症酶促饥饿，生物制药。
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[1] 
Selwan, E.M.; Finicle, B.T.; Kim, S.M.; Edinger, A.L. Attacking the supply wagons to starve cancer cells to death. FEBS Lett.,  2016, 590(7), 885-907.
[http://dx.doi.org/10.1002/1873-3468.12121] [PMID:  26938658] 
[2] 
Pavlova, N.N.; Thompson, C.B. The emerging hallmarks of cancer metabolism. Cell Metab.,  2016, 23(1), 27-47.
[http://dx.doi.org/10.1016/j.cmet.2015.12.006] [PMID:  26771115] 
[3] 
Cantor, J.R.; Panayiotou, V.; Agnello, G.; Georgiou, G.; Stone, E.M. Engineering reduced-immunogenicity enzymes for amino acid depletion therapy in cancer. Methods Enzymol.,  2012, 502, 291-319.
[http://dx.doi.org/10.1016/B978-0-12-416039-2.00015-X] [PMID:  22208990] 
[4] 
Pokrovsky, V.S.; Chepikova, O.E.; Davydov, D.Z.; Zamyatnin, A.A., Jr; Lukashev, A.N.; Lukasheva, E.V. Amino acid degrading enzymes and their application in cancer therapy. Curr. Med. Chem.,  2019, 26(3), 446-464.
[http://dx.doi.org/10.2174/0929867324666171006132729] [PMID:  28990519] 
[5] 
Lubkowski, J.; Vanegas, J.; Chan, W.K.; Lorenzi, P.L.; Weinstein, J.N.; Sukharev, S.; Fushman, D.; Rempe, S.; Anishkin, A.; Wlodawer, A. Mechanism of catalysis by l-asparaginase. Biochemistry,  2020, 59(20), 1927-1945.
[http://dx.doi.org/10.1021/acs.biochem.0c00116] [PMID:  32364696] 
[6] 
Michalska, K.; Jaskolski, M. Structural aspects of L-asparaginases, their friends and relations. Acta Biochim. Pol.,  2006, 53(4), 627-640.
[http://dx.doi.org/10.18388/abp.2006_3291] [PMID:  17143335] 
[7] 
Krishnapura, P.R.; Belur, P.D.; Subramanya, S. A critical review on properties and applications of microbial l-asparaginases. Crit. Rev. Microbiol.,  2016, 42(5), 720-737.
[PMID:  25865363] 
[8] 
Kidd, J.G. Regression of transplanted lymphomas induced in vivo by means of normal guinea pig serum. I. Course of transplanted cancers of various kinds in mice and rats given guinea pig serum, horse serum, or rabbit serum. J. Exp. Med.,  1953, 98(6), 565-582.
[http://dx.doi.org/10.1084/jem.98.6.565] [PMID:  13109110] 
[9] 
Broome, J.D. Studies on the mechanism of tumor inhibition by L-asparaginase. Effects of the enzyme on asparagine levels in the blood, normal tissues, and 6C3HED lymphomas of mice: Differences in asparagine formation and utilization in asparaginase-sensitive and -resistant lymphoma cells. J. Exp. Med.,  1968, 127(6), 1055-1072.
[http://dx.doi.org/10.1084/jem.127.6.1055] [PMID:  4871211] 
[10] 
Loeb, E.; Hill, J.M.; Hill, N.O.; MacLellan, A.; Khan, A.; Alexander, T.R.; Adachi, A. Treatment of acute leukemia with L-asparaginase. Recent Results Cancer Res.,  1970, 33, 204-218.
[http://dx.doi.org/10.1007/978-3-642-99984-0_26] [PMID:  5292717] 
[11] 
Aguayo, A.; Cortes, J.; Thomas, D.; Pierce, S.; Keating, M.; Kantarjian, H. Combination therapy with methotrexate, vincristine, polyethylene-glycol conjugated-asparaginase, and prednisone in the treatment of patients with refractory or recurrent acute lymphoblastic leukemia. Cancer,  1999, 86(7), 1203-1209.
[http://dx.doi.org/10.1002/(SICI)1097-0142(19991001)86:7<1203:AID-CNCR15>3.0.CO;2-3] [PMID:  10506705] 
[12] 
Aljewari, H.; Nader, M.; Al-Faisal, A.; Weerapreeyakul, N.; Sahapat, S. High efficiency, selectivity against cancer cell line of purified L-Asparaginase from pathogenic Escherichia coli. World Acad. Sci. Eng. Technol.,  2010, 65, 416-421.
[13] 
Ando, M.; Sugimoto, K.; Kitoh, T.; Sasaki, M.; Mukai, K.; Ando, J.; Egashira, M.; Schuster, S.M.; Oshimi, K. Selective apoptosis of natural killer-cell tumours by l-asparaginase. Br. J. Haematol.,  2005, 130(6), 860-868.
[http://dx.doi.org/10.1111/j.1365-2141.2005.05694.x] [PMID:  16156856] 
[14] 
Pieters, R.; Carroll, W.L. Biology and treatment of acute lymphoblastic leukemia. Hematol. Oncol. Clin. North Am.,  2010, 24(1), 1-18.
[http://dx.doi.org/10.1016/j.hoc.2009.11.014] [PMID:  20113893] 
[15] 
Yunis, A.A.; Arimura, G.K.; Russin, D.J. Human pancreatic carcinoma (MIA PaCa-2) in continuous culture: Sensitivity to asparaginase. Int. J. Cancer,  1977, 19(1), 128-135.
[http://dx.doi.org/10.1002/ijc.2910190118] [PMID:  832918] 
[16] 
Avramis, V.I.; Panosyan, E.H. Pharmacokinetic/pharmacodynamic relationships of asparaginase formulations: The past, the present and recommendations for the future. Clin. Pharmacokinet.,  2005, 44(4), 367-393.
[http://dx.doi.org/10.2165/00003088-200544040-00003] [PMID:  15828851] 
[17] 
Kato, M.; Manabe, A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr. Int. (Roma),  2018, 60(1), 4-12.
[http://dx.doi.org/10.1111/ped.13457] [PMID:  29143423] 
[18] 
Bhojwani, D.; Yang, J.J.; Pui, C.H. Biology of childhood acute lymphoblastic leukemia. Pediatr. Clin. North Am.,  2015, 62(1), 47-60.
[http://dx.doi.org/10.1016/j.pcl.2014.09.004] [PMID:  25435111] 
[19] 
Müller, H.J.; Boos, J. Use of L-asparaginase in childhood ALL. Crit. Rev. Oncol. Hematol.,  1998, 28(2), 97-113.
[http://dx.doi.org/10.1016/S1040-8428(98)00015-8] [PMID:  9768345] 
[20] 
Perel, Y.; Auvrignon, A.; Leblanc, T.; Vannier, J.P.; Michel, G.; Nelken, B.; Gandemer, V.; Schmitt, C.; Lamagnere, J.P.; De Lumley, L.; Bader-Meunier, B.; Couillaud, G.; Schaison, G.; Landman-Parker, J.; Thuret, I.; Dalle, J.H.; Baruchel, A.; Leverger, G.; Immunology, G.L.F.S.P.H. Impact of addition of maintenance therapy to intensive induction and consolidation chemotherapy for childhood acute myeloblastic leukemia: Results of a prospective randomized trial, LAME 89/91. Leucámie Aiqüe Myéloïde Enfant. J. Clin. Oncol.,  2002, 20(12), 2774-2782.
[http://dx.doi.org/10.1200/JCO.2002.07.300] [PMID:  12065553] 
[21] 
Willems, L.; Jacque, N.; Jacquel, A.; Neveux, N.; Maciel, T.T.; Lambert, M.; Schmitt, A.; Poulain, L.; Green, A.S.; Uzunov, M.; Kosmider, O.; Radford-Weiss, I.; Moura, I.C.; Auberger, P.; Ifrah, N.; Bardet, V.; Chapuis, N.; Lacombe, C.; Mayeux, P.; Tamburini, J.; Bouscary, D. Inhibiting glutamine uptake represents an attractive new strategy for treating acute myeloid leukemia. Blood,  2013, 122(20), 3521-3532.
[http://dx.doi.org/10.1182/blood-2013-03-493163] [PMID:  24014241] 
[22] 
Yamaguchi, M.; Kwong, Y.L.; Kim, W.S.; Maeda, Y.; Hashimoto, C.; Suh, C.; Izutsu, K.; Ishida, F.; Isobe, Y.; Sueoka, E.; Suzumiya, J.; Kodama, T.; Kimura, H.; Hyo, R.; Nakamura, S.; Oshimi, K.; Suzuki, R.; Phase, I.I. Phase II study of SMILE chemotherapy for newly diagnosed stage IV, relapsed, or refractory extranodal natural killer (NK)/T-cell lymphoma, nasal type: The NK-Cell Tumor Study Group study. J. Clin. Oncol.,  2011, 29(33), 4410-4416.
[http://dx.doi.org/10.1200/JCO.2011.35.6287] [PMID:  21990393] 
[23] 
Dufour, E.; Gay, F.; Aguera, K.; Scoazec, J.Y.; Horand, F.; Lorenzi, P.L.; Godfrin, Y. Pancreatic tumor sensitivity to plasma L-asparagine starvation. Pancreas,  2012, 41(6), 940-948.
[http://dx.doi.org/10.1097/MPA.0b013e318247d903] [PMID:  22513289] 
[24] 
Lorenzi, P.L.; Llamas, J.; Gunsior, M.; Ozbun, L.; Reinhold, W.C.; Varma, S.; Ji, H.; Kim, H.; Hutchinson, A.A.; Kohn, E.C.; Goldsmith, P.K.; Birrer, M.J.; Weinstein, J.N. Asparagine synthetase is a predictive biomarker of L-asparaginase activity in ovarian cancer cell lines. Mol. Cancer Ther.,  2008, 7(10), 3123-3128.
[http://dx.doi.org/10.1158/1535-7163.MCT-08-0589] [PMID:  18852115] 
[25] 
Lorenzi, P.L.; Reinhold, W.C.; Rudelius, M.; Gunsior, M.; Shankavaram, U.; Bussey, K.J.; Scherf, U.; Eichler, G.S.; Martin, S.E.; Chin, K.; Gray, J.W.; Kohn, E.C.; Horak, I.D.; Von Hoff, D.D.; Raffeld, M.; Goldsmith, P.K.; Caplen, N.J.; Weinstein, J.N. Asparagine synthetase as a causal, predictive biomarker for L-asparaginase activity in ovarian cancer cells. Mol. Cancer Ther.,  2006, 5(11), 2613-2623.
[http://dx.doi.org/10.1158/1535-7163.MCT-06-0447] [PMID:  17088436] 
[26] 
Pasut, G.; Sergi, M.; Veronese, F.M. Anti-cancer PEG-enzymes: 30 years old, but still a current approach. Adv. Drug Deliv. Rev.,  2008, 60(1), 69-78.
[http://dx.doi.org/10.1016/j.addr.2007.04.018] [PMID:  17869378] 
[27] 
Soares, A.L.; Guimarães, G.M.; Polakiewicz, B.; de Moraes Pitombo, R.N.; Abrahão-Neto, J. Effects of polyethylene glycol attachment on physicochemical and biological stability of E. coli L-asparaginase. Int. J. Pharm.,  2002, 237(1-2), 163-170.
[http://dx.doi.org/10.1016/S0378-5173(02)00046-7] [PMID:  11955814] 
[28] 
Melik-Nubarov, N.S.; Grozdova, I.D.; Lomakina, G.Y.; Pokrovskaya, M.V.; Pokrovski, V.S.; Aleksandrova, S.S.; Abakumova, O.Y.; Podobed, O.V.; Grishin, D.V.; Sokolov, N.N. PEGylated recombinant L-asparaginase from Erwinia carotovora: Production, properties, and potential applications. Prikl. Biokhim. Mikrobiol.,  2017, 53(2), 164-172.
[PMID:  29508977] 
[29] 
Thomas, X.; Le Jeune, C. Erythrocyte encapsulated l-asparaginase (GRASPA) in acute leukemia. Int. J. Hematol. Oncol.,  2016, 5(1), 11-25.
[http://dx.doi.org/10.2217/ijh-2016-0002] [PMID:  30302200] 
[30] 
Brito, A.E.M.; Pessoa, A., Jr; Converti, A.; Rangel-Yagui, C.O.; Silva, J.A.D.; Apolinário, A.C. Poly (lactic-co-glycolic acid) nanospheres allow for high l-asparaginase encapsulation yield and activity. Mater. Sci. Eng. C,  2019, 98, 524-534.
[http://dx.doi.org/10.1016/j.msec.2019.01.003] [PMID:  30813054] 
[31] 
Wan, S.; He, D.; Yuan, Y.; Yan, Z.; Zhang, X.; Zhang, J. Chitosan-modified lipid nanovesicles for efficient systemic delivery of l-asparaginase. Colloids Surf. B Biointerfaces,  2016, 143, 278-284.
[http://dx.doi.org/10.1016/j.colsurfb.2016.03.046] [PMID:  27022867] 
[32] 
Cantor, J.R.; Stone, E.M.; Chantranupong, L.; Georgiou, G. The human asparaginase-like protein 1 hASRGL1 is an Ntn hydrolase with beta-aspartyl peptidase activity. Biochemistry,  2009, 48(46), 11026-11031.
[http://dx.doi.org/10.1021/bi901397h] [PMID:  19839645] 
[33] 
Saarela, J.; Oinonen, C.; Jalanko, A.; Rouvinen, J.; Peltonen, L. Autoproteolytic activation of human aspartylglucosaminidase. Biochem. J.,  2004, 378(Pt 2), 363-371.
[http://dx.doi.org/10.1042/bj20031496] [PMID:  14616088] 
[34] 
Belviso, S.; Iuliano, R.; Amato, R.; Perrotti, N.; Menniti, M. The human asparaginase enzyme (ASPG) inhibits growth in leukemic cells. PLoS One,  2017, 12(5)e0178174
[http://dx.doi.org/10.1371/journal.pone.0178174] [PMID:  28542249] 
[35] 
Beckett, A.; Gervais, D. What makes a good new therapeutic L-asparaginase? World J. Microbiol. Biotechnol.,  2019, 35(10), 152.
[http://dx.doi.org/10.1007/s11274-019-2731-9] [PMID:  31552479] 
[36] 
Al-Dulimi, A.G.; Al-Saffar, A.Z.; Sulaiman, G.M.; Khalil, K.A.A.; Khashan, K.S.; Al-Shmgani, H.S.A.; Ahmed, E.M. Immobilization of L-asparaginase on gold nanoparticles for novel drug delivery approach as anti-cancer agent against human breast carcinoma cells. J. Mater. Res.,  2020, 9(6), 15394-15411.
[37] 
Xiong, L.; Teng, J.L.L.; Botelho, M.G.; Lo, R.C.; Lau, S.K.P.; Woo, P.C.Y. Arginine metabolism in bacterial pathogenesis and cancer therapy. Int. J. Mol. Sci.,  2016, 17(3), 363.
[http://dx.doi.org/10.3390/ijms17030363] [PMID:  26978353] 
[38] 
Dillon, B.J.; Prieto, V.G.; Curley, S.A.; Ensor, C.M.; Holtsberg, F.W.; Bomalaski, J.S.; Clark, M.A. Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: A method for identifying cancers sensitive to arginine deprivation. Cancer,  2004, 100(4), 826-833.
[http://dx.doi.org/10.1002/cncr.20057] [PMID:  14770441] 
[39] 
Qiu, F.; Huang, J.; Sui, M. Targeting arginine metabolism pathway to treat arginine-dependent cancers. Cancer Lett.,  2015, 364(1), 1-7.
[http://dx.doi.org/10.1016/j.canlet.2015.04.020] [PMID:  25917076] 
[40] 
Fernandes, H.S.; Silva Teixeira, C.S.; Fernandes, P.A.; Ramos, M.J.; Cerqueira, N.M. Amino acid deprivation using enzymes as a targeted therapy for cancer and viral infections. Expert Opin. Ther. Pat.,  2017, 27(3), 283-297.
[http://dx.doi.org/10.1080/13543776.2017.1254194] [PMID:  27813440] 
[41] 
Bobak, Y.P.; Vynnytska, B.O.; Kurlishchuk, Y.V.; Sibirny, A.A.; Stasyk, O.V. Cancer cell sensitivity to arginine deprivation in vitro is not determined by endogenous levels of arginine metabolic enzymes. Cell Biol. Int.,  2010, 34(11), 1085-1089.
[http://dx.doi.org/10.1042/CBI20100451] [PMID:  20653567] 
[42] 
Han, R.Z.; Xu, G.C.; Dong, J.J.; Ni, Y. Arginine deiminase: Recent advances in discovery, crystal structure, and protein engineering for improved properties as an anti-tumor drug. Appl. Microbiol. Biotechnol.,  2016, 100(11), 4747-4760.
[http://dx.doi.org/10.1007/s00253-016-7490-z] [PMID:  27087524] 
[43] 
Miyazaki, K.; Takaku, H.; Umeda, M.; Fujita, T.; Huang, W.D.; Kimura, T.; Yamashita, J.; Horio, T. Potent growth inhibition of human tumor cells in culture by arginine deiminase purified from a culture medium of a Mycoplasma-infected cell line. Cancer Res.,  1990, 50(15), 4522-4527.
[PMID:  2164440] 
[44] 
Patil, M.D.; Bhaumik, J.; Babykutty, S.; Banerjee, U.C.; Fukumura, D. Arginine dependence of tumor cells: Targeting a chink in cancer’s armor. Oncogene,  2016, 35(38), 4957-4972.
[http://dx.doi.org/10.1038/onc.2016.37] [PMID:  27109103] 
[45] 
Holtsberg, F.W.; Ensor, C.M.; Steiner, M.R.; Bomalaski, J.S.; Clark, M.A. Poly(ethylene glycol) (PEG) conjugated arginine deiminase: Effects of PEG formulations on its pharmacological properties. J. Control. Release,  2002, 80(1-3), 259-271.
[http://dx.doi.org/10.1016/S0168-3659(02)00042-1] [PMID:  11943403] 
[46] 
Chow, A.K.; Yau, S.W.; Ng, L. Novel molecular targets in hepatocellular carcinoma. World J. Clin. Oncol.,  2020, 11(8), 589-605.
[http://dx.doi.org/10.5306/wjco.v11.i8.589] [PMID:  32879846] 
[47] 
Fung, M.K.L.; Chan, G.C.F. Drug-induced amino acid deprivation as strategy for cancer therapy. J. Hematol. Oncol.,  2017, 10(1), 144.
[http://dx.doi.org/10.1186/s13045-017-0509-9] [PMID:  28750681] 
[48] 
Dhankhar, R.; Gulati, P.; Kumar, S.; Kapoor, R.K. Arginine-lowering enzymes against cancer: A technocommercial analysis through patent landscape. Expert Opin. Ther. Pat.,  2018, 28(8), 603-614.
[http://dx.doi.org/10.1080/13543776.2018.1508452] [PMID:  30092168] 
[49] 
Philip, R.; Campbell, E.; Wheatley, D.N. Arginine deprivation, growth inhibition and tumour cell death: 2. Enzymatic degradation of arginine in normal and malignant cell cultures. Br. J. Cancer,  2003, 88(4), 613-623.
[http://dx.doi.org/10.1038/sj.bjc.6600681] [PMID:  12592378] 
[50] 
Wheatley, D.N.; Campbell, E. Arginine catabolism, liver extracts and cancer. Pathol. Oncol. Res.,  2002, 8(1), 18-25.
[http://dx.doi.org/10.1007/BF03033696] [PMID:  11994758] 
[51] 
Li, L.H.; Wang, Y.; Chen, J.; Cheng, B.; Hu, J.H.; Zhou, Y.H.; Gao, X.; Gao, L.C.; Mei, X.F.; Sun, M.Y.; Zhang, Z.M.; Song, H.F. An Engineered Arginase FC Protein Inhibits Tumor Growth in vitro and in vivo. Evidence-Based Complementary and Alternative Medicine, 2013.
[52] 
Stone, E.M.; Glazer, E.S.; Chantranupong, L.; Cherukuri, P.; Breece, R.M.; Tierney, D.L.; Curley, S.A.; Iverson, B.L.; Georgiou, G. Replacing Mn(2+) with Co(2+) in human arginase i enhances cytotoxicity toward l-arginine auxotrophic cancer cell lines. ACS Chem. Biol.,  2010, 5(3), 333-342.
[http://dx.doi.org/10.1021/cb900267j] [PMID:  20050660] 
[53] 
Yau, T.; Cheng, P.N.; Chan, P.; Chen, L.; Yuen, J.; Pang, R.; Fan, S.T.; Wheatley, D.N.; Poon, R.T. Preliminary efficacy, safety, pharmacokinetics, pharmacodynamics and quality of life study of pegylated recombinant human arginase 1 in patients with advanced hepatocellular carcinoma. Invest. New Drugs,  2015, 33(2), 496-504.
[http://dx.doi.org/10.1007/s10637-014-0200-8] [PMID:  25666409] 
[54] 
Fultang, L.; Vardon, A.; De Santo, C.; Mussai, F. Molecular basis and current strategies of therapeutic arginine depletion for cancer. Int. J. Cancer,  2016, 139(3), 501-509.
[http://dx.doi.org/10.1002/ijc.30051] [PMID:  26913960] 
[55] 
Chung, S.F.; Kim, C.F.; Tam, S.Y.; Choi, M.C.; So, P.K.; Wong, K.Y.; Leung, Y.C.; Lo, W.H. A bioengineered arginine-depleting enzyme as a long-lasting therapeutic agent against cancer. Appl. Microbiol. Biotechnol.,  2020, 104(9), 3921-3934.
[http://dx.doi.org/10.1007/s00253-020-10484-4] [PMID:  32144472] 
[56] 
Schieber, M.; Chandel, N.S. ROS function in redox signaling and oxidative stress. Curr. Biol.,  2014, 24(10), R453-R462.
[http://dx.doi.org/10.1016/j.cub.2014.03.034] [PMID:  24845678] 
[57] 
Hoffman, R.M. Methionine Dependence of Cancer and Aging: Methods and protocols; Humana Press: New York, NY, 2019. 
[http://dx.doi.org/10.1007/978-1-4939-8796-2] 
[58] 
Chaturvedi, S.; Hoffman, R.M.; Bertino, J.R. Exploiting methionine restriction for cancer treatment. Biochem. Pharmacol.,  2018, 154, 170-173.
[http://dx.doi.org/10.1016/j.bcp.2018.05.003] [PMID:  29733806] 
[59] 
Cavuoto, P.; Fenech, M.F. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension. Cancer Treat. Rev.,  2012, 38(6), 726-736.
[http://dx.doi.org/10.1016/j.ctrv.2012.01.004] [PMID:  22342103] 
[60] 
El-Sayed, A.S. Microbial L-methioninase: Production, molecular characterization, and therapeutic applications. Appl. Microbiol. Biotechnol.,  2010, 86(2), 445-467.
[http://dx.doi.org/10.1007/s00253-009-2303-2] [PMID:  20146062] 
[61] 
Morozova, E.A.; Kulikova, V.V.; Yashin, D.V.; Anufrieva, N.V.; Anisimova, N.Y.; Revtovich, S.V.; Kotlov, M.I.; Belyi, Y.F.; Pokrovsky, V.S.; Demidkina, T.V. Kinetic parameters and cytotoxic activity of recombinant methionine γ-lyase from Clostridium tetani, Clostridium sporogenes, Porphyromonas gingivalis and Citrobacter freundii. Acta Naturae,  2013, 5(3), 92-98.
[http://dx.doi.org/10.32607/20758251-2013-5-3-92-98] [PMID:  24303205] 
[62] 
Hoffman, R.M. Development of recombinant methioninase to target the general cancer-specific metabolic defect of methionine dependence: A 40-year odyssey. Expert Opin. Biol. Ther.,  2015, 15(1), 21-31.
[http://dx.doi.org/10.1517/14712598.2015.963050] [PMID:  25439528] 
[63] 
Poirson-Bichat, F.; Gonçalves, R.A.; Miccoli, L.; Dutrillaux, B.; Poupon, M.F. Methionine depletion enhances the antitumoral efficacy of cytotoxic agents in drug-resistant human tumor xenografts. Clin. Cancer Res.,  2000, 6(2), 643-653.
[PMID:  10690550] 
[64] 
Wang, Z.; Yip, L.Y.; Lee, J.H.J.; Wu, Z.; Chew, H.Y.; Chong, P.K.W.; Teo, C.C.; Ang, H.Y.; Peh, K.L.E.; Yuan, J.; Ma, S.; Choo, L.S.K.; Basri, N.; Jiang, X.; Yu, Q.; Hillmer, A.M.; Lim, W.T.; Lim, T.K.H.; Takano, A.; Tan, E.H.; Tan, D.S.W.; Ho, Y.S.; Lim, B.; Tam, W.L. Methionine is a metabolic dependency of tumor-initiating cells. Nat. Med.,  2019, 25(5), 825-837.
[http://dx.doi.org/10.1038/s41591-019-0423-5] [PMID:  31061538] 
[65] 
Hu, J.; Cheung, N.K.V. Methionine depletion with recombinant methioninase: in vitro and in vivo efficacy against neuroblastoma and its synergism with chemotherapeutic drugs. Int. J. Cancer,  2009, 124(7), 1700-1706.
[http://dx.doi.org/10.1002/ijc.24104] [PMID:  19089915] 
[66] 
Kokkinakis, D.M.; Hoffman, R.M.; Frenkel, E.P.; Wick, J.B.; Han, Q.; Xu, M.; Tan, Y.; Schold, S.C. Synergy between methionine stress and chemotherapy in the treatment of brain tumor xenografts in athymic mice. Cancer Res.,  2001, 61(10), 4017-4023.
[PMID:  11358820] 
[67] 
Lu, W.C.; Saha, A.; Yan, W.; Garrison, K.; Lamb, C.; Pandey, R.; Irani, S.; Lodi, A.; Lu, X.; Tiziani, S.; Zhang, Y.J.; Georgiou, G.; DiGiovanni, J.; Stone, E. Enzyme-mediated depletion of serum l-Met abrogates prostate cancer growth via multiple mechanisms without evidence of systemic toxicity. Proc. Natl. Acad. Sci. USA,  2020, 117(23), 13000-13011.
[http://dx.doi.org/10.1073/pnas.1917362117] [PMID:  32434918] 
[68] 
Sharma, B.; Singh, S.; Kanwar, S.S. L-Methionase: A therapeutic enzyme to treat malignancies. BioMed Res. Int.,  2014, 2014506287
[http://dx.doi.org/10.1155/2014/506287] [PMID:  25250324] 
[69] 
Raboni, S.; Revtovich, S.; Demitri, N.; Giabbai, B.; Storici, P.; Cocconcelli, C.; Faggiano, S.; Rosini, E.; Pollegioni, L.; Galati, S.; Buschini, A.; Morozova, E.; Kulikova, V.; Nikulin, A.; Gabellieri, E.; Cioni, P.; Demidkina, T.; Mozzarelli, A. Engineering methionine γ-lyase from Citrobacter freundii for anticancer activity. Biochim. Biophys. Acta. Proteins Proteomics,  2018, 1866(12), 1260-1270.
[http://dx.doi.org/10.1016/j.bbapap.2018.09.011] [PMID:  30268810] 
[70] 
Guillen, K.P.; Kurkjian, C.; Harrison, R.G. Targeted enzyme prodrug therapy for metastatic prostate cancer-a comparative study of L-methioninase, purine nucleoside phosphorylase, and cytosine deaminase. J. Biomed. Sci.,  2014, 21, 65.
[http://dx.doi.org/10.1186/s12929-014-0065-3] [PMID:  25047949] 
[71] 
Van Rite, B.D.; Krais, J.J.; Cherry, M.; Sikavitsas, V.I.; Kurkjian, C.; Harrison, R.G. Antitumor activity of an enzyme prodrug therapy targeted to the breast tumor vasculature. Cancer Invest.,  2013, 31(8), 505-510.
[http://dx.doi.org/10.3109/07357907.2013.840383] [PMID:  24083814] 
[72] 
Yang, Z.; Wang, J.; Lu, Q.; Xu, J.; Kobayashi, Y.; Takakura, T.; Takimoto, A.; Yoshioka, T.; Lian, C.; Chen, C.; Zhang, D.; Zhang, Y.; Li, S.; Sun, X.; Tan, Y.; Yagi, S.; Frenkel, E.P.; Hoffman, R.M. PEGylation confers greatly extended half-life and attenuated immunogenicity to recombinant methioninase in primates. Cancer Res.,  2004, 64(18), 6673-6678.
[http://dx.doi.org/10.1158/0008-5472.CAN-04-1822] [PMID:  15374983] 
[73] 
Hoffman, R.M. PEG-methioninase. Adv. Exp. Med. Biol.,  2003, 519, 69-79.
[http://dx.doi.org/10.1007/0-306-47932-X_5] [PMID:  12675209] 
[74] 
Xin, L.; Caot, J.Q.; Liu, C.; Zeng, F.; Cheng, H.; Hu, X.Y.; Shao, J.H. Evaluation of rMETase-Loaded Stealth PLGA/Liposomes Modified with Anti-CAGE scFV for Treatment of Gastric Carcinoma. J. Biomed. Nanotechnol.,  2015, 11(7), 1153-1161.
[http://dx.doi.org/10.1166/jbn.2015.2062] [PMID:  26307838] 
[75] 
Morozova, E.A.; Kulikova, V.V.; Faggiano, S.; Raboni, S.; Gabellieri, E.; Cioni, P.; Anufrieva, N.V.; Revtovich, S.V.; Demidkina, T.; Mozzarelli, A. Soluble and Nanoporous Silica Gel-Entrapped C. freundii Methionine γ-Lyase. J. Nanosci. Nanotechnol.,  2018, 18(3), 2210-2219.
[http://dx.doi.org/10.1166/jnn.2018.14333] [PMID:  29448748] 
[76] 
Miki, K.; Al-Refaie, W.; Xu, M.; Jiang, P.; Tan, Y.; Bouvet, M.; Zhao, M.; Gupta, A.; Chishima, T.; Shimada, H.; Makuuchi, M.; Moossa, A.R.; Hoffman, R.M. Methioninase gene therapy of human cancer cells is synergistic with recombinant methioninase treatment. Cancer Res.,  2000, 60(10), 2696-2702.
[PMID:  10825143] 
[77] 
Stone, E.; Paley, O.; Hu, J.; Ekerdt, B.; Cheung, N.K.; Georgiou, G. De novo engineering of a human cystathionine-γ-lyase for systemic (L)-Methionine depletion cancer therapy. ACS Chem. Biol.,  2012, 7(11), 1822-1829.
[http://dx.doi.org/10.1021/cb300335j] [PMID:  22963240] 
[78] 
Gay, F.; Aguera, K.; Sénéchal, K.; Tainturier, A.; Berlier, W.; Maucort-Boulch, D.; Honnorat, J.; Horand, F.; Godfrin, Y.; Bourgeaux, V. Methionine tumor starvation by erythrocyte-encapsulated methionine gamma-lyase activity controlled with per os vitamin B6. Cancer Med.,  2017, 6(6), 1437-1452.
[http://dx.doi.org/10.1002/cam4.1086] [PMID:  28544589] 
[79] 
Bak, D.W.; Bechtel, T.J.; Falco, J.A.; Weerapana, E. Cysteine reactivity across the subcellular universe. Curr. Opin. Chem. Biol.,  2019, 48, 96-105.
[http://dx.doi.org/10.1016/j.cbpa.2018.11.002] [PMID:  30508703] 
[80] 
Dixon, S.J.; Lemberg, K.M.; Lamprecht, M.R.; Skouta, R.; Zaitsev, E.M.; Gleason, C.E.; Patel, D.N.; Bauer, A.J.; Cantley, A.M.; Yang, W.S.; Morrison, B., III; Stockwell, B.R. Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell,  2012, 149(5), 1060-1072.
[http://dx.doi.org/10.1016/j.cell.2012.03.042] [PMID:  22632970] 
[81] 
Cramer, S.L.; Saha, A.; Liu, J.; Tadi, S.; Tiziani, S.; Yan, W.; Triplett, K.; Lamb, C.; Alters, S.E.; Rowlinson, S.; Zhang, Y.J.; Keating, M.J.; Huang, P.; DiGiovanni, J.; Georgiou, G.; Stone, E. Systemic depletion of L-cyst(e)ine with cyst(e)inase increases reactive oxygen species and suppresses tumor growth. Nat. Med.,  2017, 23(1), 120-127.
[http://dx.doi.org/10.1038/nm.4232] [PMID:  27869804] 
[82] 
Wang, W.; Green, M.; Choi, J.E.; Gijón, M.; Kennedy, P.D.; Johnson, J.K.; Liao, P.; Lang, X.; Kryczek, I.; Sell, A.; Xia, H.; Zhou, J.; Li, G.; Li, J.; Li, W.; Wei, S.; Vatan, L.; Zhang, H.; Szeliga, W.; Gu, W.; Liu, R.; Lawrence, T.S.; Lamb, C.; Tanno, Y.; Cieslik, M.; Stone, E.; Georgiou, G.; Chan, T.A.; Chinnaiyan, A.; Zou, W. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature,  2019, 569(7755), 270-274.
[http://dx.doi.org/10.1038/s41586-019-1170-y] [PMID:  31043744] 
[83] 
Bonifacio, V.D.B.; Pereira, S.A.; Serpa, J.; Vicente, J.B. Cysteine metabolic circuitries: druggable targets in cancer. Br. J. Cancer, 2020.
[PMID:  33223534] 
[84] 
Kshattry, S.; Saha, A.; Gries, P.; Tiziani, S.; Stone, E.; Georgiou, G.; DiGiovanni, J. Enzyme-mediated depletion of l-cyst(e)ine synergizes with thioredoxin reductase inhibition for suppression of pancreatic tumor growth. NPJ Precis Oncol,  2019, 3, 16.
[http://dx.doi.org/10.1038/s41698-019-0088-z] [PMID:  31231686] 
[85] 
Jones, C.L.; Stevens, B.M.; D’Alessandro, A.; Culp-Hill, R.; Reisz, J.A.; Pei, S.; Gustafson, A.; Khan, N.; DeGregori, J.; Pollyea, D.A.; Jordan, C.T. Cysteine depletion targets leukemia stem cells through inhibition of electron transport complex II. Blood,  2019, 134(4), 389-394.
[http://dx.doi.org/10.1182/blood.2019898114] [PMID:  31101624] 
[86] 
Graham, N.A.; Tahmasian, M.; Kohli, B.; Komisopoulou, E.; Zhu, M.; Vivanco, I.; Teitell, M.A.; Wu, H.; Ribas, A.; Lo, R.S.; Mellinghoff, I.K.; Mischel, P.S.; Graeber, T.G. Glucose deprivation activates a metabolic and signaling amplification loop leading to cell death. Mol. Syst. Biol.,  2012, 8, 589.
[http://dx.doi.org/10.1038/msb.2012.20] [PMID:  22735335] 
[87] 
Liu, Y.; Nan, X.; Shi, W.; Liu, X.; He, Z.; Sun, Y.N.; Ge, D.T. A glucose biosensor based on the immobilization of glucose oxidase and Au nanocomposites with polynorepinephrine. RSC Advances,  2019, 9(29), 16439-16446.
[http://dx.doi.org/10.1039/C9RA02054C] 
[88] 
Yu, S.; Chen, Z.; Zeng, X.; Chen, X.; Gu, Z. Advances in nanomedicine for cancer starvation therapy. Theranostics,  2019, 9(26), 8026-8047.
[http://dx.doi.org/10.7150/thno.38261] [PMID:  31754379] 
[89] 
Wang, C.H.; Yang, J.X.; Dong, C.Y.; Shi, S. Glucose Oxidase-Related Cancer Therapies. Adv. Ther.,  2020, 3(10)
[90] 
Bankar, S.B.; Bule, M.V.; Singhal, R.S.; Ananthanarayan, L. Glucose oxidase--an overview. Biotechnol. Adv.,  2009, 27(4), 489-501.
[http://dx.doi.org/10.1016/j.biotechadv.2009.04.003] [PMID:  19374943] 
[91] 
Dinda, S.; Sarkar, S.; Das, P.K. Glucose oxidase mediated targeted cancer-starving therapy by biotinylated self-assembled vesicles. Chem. Commun. (Camb.),  2018, 54(71), 9929-9932.
[http://dx.doi.org/10.1039/C8CC03599G] [PMID:  30116805] 
[92] 
Wang, M.; Wang, D.; Chen, Q.; Li, C.; Li, Z.; Lin, J. Recent advances in glucose-oxidase-based nanocomposites for tumor therapy. Small,  2019, 15(51)e1903895
[http://dx.doi.org/10.1002/smll.201903895] [PMID:  31747128] 
[93] 
Zhang, Y.H.; Qiu, W.X.; Zhang, M.; Zhang, L.; Zhang, X.Z. MnO2 motor: A prospective cancer-starving therapy promoter. ACS Appl. Mater. Interfaces,  2018, 10(17), 15030-15039.
[http://dx.doi.org/10.1021/acsami.8b01818] [PMID:  29633614] 
[94] 
Sun, D.; Qi, G.; Ma, K.; Qu, X.; Xu, W.; Xu, S.; Jin, Y. Tumor microenvironment-activated degradable multifunctional
nanoreactor for synergistic cancer therapy and glucose
SERS feedback. iScience, 2020, 23(7), 101274.. 
[95] 
Pastan, I.; Hassan, R.; Fitzgerald, D.J.; Kreitman, R.J. Immunotoxin therapy of cancer. Nat. Rev. Cancer,  2006, 6(7), 559-565.
[http://dx.doi.org/10.1038/nrc1891] [PMID:  16794638] 
[96] 
Pastan, I.; Hassan, R.; FitzGerald, D.J.; Kreitman, R.J. Immunotoxin treatment of cancer. Annu. Rev. Med.,  2007, 58, 221-237.
[http://dx.doi.org/10.1146/annurev.med.58.070605.115320] [PMID:  17059365] 
[97] 
Akbari, B.; Farajnia, S.; Ahdi Khosroshahi, S.; Safari, F.; Yousefi, M.; Dariushnejad, H.; Rahbarnia, L. Immunotoxins in cancer therapy: Review and update. Int. Rev. Immunol.,  2017, 36(4), 207-219.
[http://dx.doi.org/10.1080/08830185.2017.1284211] [PMID:  28282218] 
[98] 
Allahyari, H.; Heidari, S.; Ghamgosha, M.; Saffarian, P.; Amani, J. Immunotoxin: A new tool for cancer therapy. Tumour Biol.,  2017, 39(2)1010428317692226
[http://dx.doi.org/10.1177/1010428317692226] [PMID:  28218037] 
[99] 
Wong, J.H.; Bao, H.; Ng, T.B.; Chan, H.H.L.; Ng, C.C.W.; Man, G.C.W.; Wang, H.; Guan, S.; Zhao, S.; Fang, E.F.; Rolka, K.; Liu, Q.; Li, C.; Sha, O.; Xia, L. New ribosome-inactivating proteins and other proteins with protein synthesis-inhibiting activities. Appl. Microbiol. Biotechnol.,  2020, 104(10), 4211-4226.
[http://dx.doi.org/10.1007/s00253-020-10457-7] [PMID:  32193575] 
[100] 
Rust, A.; Partridge, L.J.; Davletov, B.; Hautbergue, G.M. The use of plant-derived ribosome inactivating proteins in immunotoxin development: past, present and future generations. Toxins (Basel),  2017, 9(11), 9.
[http://dx.doi.org/10.3390/toxins9110344] [PMID:  29076988] 
[101] 
Blakey, D.C.; Watson, G.J.; Knowles, P.P.; Thorpe, P.E. Effect of chemical deglycosylation of ricin A chain on the in vivo fate and cytotoxic activity of an immunotoxin composed of ricin A chain and anti-Thy 1.1 antibody. Cancer Res.,  1987, 47(4), 947-952.
[PMID:  3492271] 
[102] 
Lu, J-Q.; Zhu, Z-N.; Zheng, Y-T.; Shaw, P-C. Engineering of ribosome-inactivating proteins for improving pharmacological properties. Toxins (Basel),  2020, 12(3), 12.
[http://dx.doi.org/10.3390/toxins12030167] [PMID:  32182799] 
[103] 
Cizeau, J.; Grenkow, D.M.; Brown, J.G.; Entwistle, J.; MacDonald, G.C. Engineering and biological characterization of VB6-845, an anti-EpCAM immunotoxin containing a T-cell epitope-depleted variant of the plant toxin bouganin. J. Immunother.,  2009, 32(6), 574-584.
[http://dx.doi.org/10.1097/CJI.0b013e3181a6981c] [PMID:  19483652] 
[104] 
Mazor, R.; Eberle, J.A.; Hu, X.; Vassall, A.N.; Onda, M.; Beers, R.; Lee, E.C.; Kreitman, R.J.; Lee, B.; Baker, D.; King, C.; Hassan, R.; Benhar, I.; Pastan, I. Recombinant immunotoxin for cancer treatment with low immunogenicity by identification and silencing of human T-cell epitopes. Proceedings of the National Academy of Sciences,  2014, p. 111.
[http://dx.doi.org/10.1073/pnas.1405153111] 
[105] 
Cheung, L.S.; Fu, J.; Kumar, P.; Kumar, A.; Urbanowski, M.E.; Ihms, E.A.; Parveen, S.; Bullen, C.K.; Patrick, G.J.; Harrison, R.; Murphy, J.R.; Pardoll, D.M.; Bishai, W.R. Second-generation IL-2 receptor-targeted diphtheria fusion toxin exhibits antitumor activity and synergy with anti–PD-1 in melanoma. Proceedings of the National Academy of Sciences,  2019, p. 116.
[http://dx.doi.org/10.1073/pnas.1815087116] 
[106] 
Zuppone, S.; Fabbrini, M.S.; Vago, R. Hosts for Hostile Protein Production: The Challenge of Recombinant Immunotoxin Expression. Biomedicines,  2019, 7(2), 7.
[http://dx.doi.org/10.3390/biomedicines7020038] [PMID:  31108917] 
[107] 
Olsen, E.; Duvic, M.; Frankel, A.; Kim, Y.; Martin, A.; Vonderheid, E.; Jegasothy, B.; Wood, G.; Gordon, M.; Heald, P.; Oseroff, A.; Pinter-Brown, L.; Bowen, G.; Kuzel, T.; Fivenson, D.; Foss, F.; Glode, M.; Molina, A.; Knobler, E.; Stewart, S.; Cooper, K.; Stevens, S.; Craig, F.; Reuben, J.; Bacha, P.; Nichols, J. Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol.,  2001, 19(2), 376-388.
[http://dx.doi.org/10.1200/JCO.2001.19.2.376] [PMID:  11208829] 
[108] 
Jen, E.Y.; Gao, X.; Li, L.; Zhuang, L.; Simpson, N.E.; Aryal, B.; Wang, R.; Przepiorka, D.; Shen, Y.L.; Leong, R.; Liu, C.; Sheth, C.M.; Bowen, S.; Goldberg, K.B.; Farrell, A.T.; Blumenthal, G.M.; Pazdur, R. FDA Approval summary: tagraxofusperzs for treatment of blastic plasmacytoid dendritic cell neoplasm. Clin. Cancer Res.,  2020, 26(3), 532-536.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-2329] [PMID:  31548341] 
[109] 
Kreitman, R.J.; Dearden, C.; Zinzani, P.L.; Delgado, J.; Karlin, L.; Robak, T.; Gladstone, D.E.; le Coutre, P.; Dietrich, S.; Gotic, M.; Larratt, L.; Offner, F.; Schiller, G.; Swords, R.; Bacon, L.; Bocchia, M.; Bouabdallah, K.; Breems, D.A.; Cortelezzi, A.; Dinner, S.; Doubek, M.; Gjertsen, B.T.; Gobbi, M.; Hellmann, A.; Lepretre, S.; Maloisel, F.; Ravandi, F.; Rousselot, P.; Rummel, M.; Siddiqi, T.; Tadmor, T.; Troussard, X.; Yi, C.A.; Saglio, G.; Roboz, G.J.; Balic, K.; Standifer, N.; He, P.; Marshall, S.; Wilson, W.; Pastan, I.; Yao, N-S.; Giles, F. Moxetumomab pasudotox in relapsed/refractory hairy cell leukemia. Leukemia,  2018, 32(8), 1768-1777.
[http://dx.doi.org/10.1038/s41375-018-0210-1] [PMID:  30030507] 
[110] 
Mazor, R.; King, E.M.; Onda, M.; Cuburu, N.; Addissie, S.; Crown, D.; Liu, X-F.; Kishimoto, T.K.; Pastan, I. Tolerogenic nanoparticles restore the antitumor activity of recombinant immunotoxins by mitigating immunogenicity. Proceedings of the National Academy of Sciences,  2018, p. 115.
[http://dx.doi.org/10.1073/pnas.1717063115] 
[111] 
Tang, Y.; Liang, J.; Wu, A.; Chen, Y.; Zhao, P.; Lin, T.; Zhang, M.; Xu, Q.; Wang, J.; Huang, Y. Co-delivery of trichosanthin and albendazole by nano-self-assembly for overcoming tumor multidrug-resistance and metastasis. ACS Appl. Mater. Interfaces,  2017, 9(32), 26648-26664.
[http://dx.doi.org/10.1021/acsami.7b05292] [PMID:  28741923] 
[112] 
Kim, J-S.; Jun, S-Y.; Kim, Y-S. Critical Issues in the Development of Immunotoxins for Anticancer Therapy. J. Pharm. Sci.,  2020, 109(1), 104-115.
[http://dx.doi.org/10.1016/j.xphs.2019.10.037] [PMID:  31669121] 
[113] 
Gotte, G.; Menegazzi, M. Biological activities of secretory rnases: focus on their oligomerization to design antitumor drugs. Front. Immunol.,  2019, 10, 2626.
[http://dx.doi.org/10.3389/fimmu.2019.02626] [PMID:  31849926] 
[114] 
De Lorenzo, C.; D’Alessio, G. From immunotoxins to immunoRNases. Curr. Pharm. Biotechnol.,  2008, 9(3), 210-214.
[http://dx.doi.org/10.2174/138920108784567254] [PMID:  18673286] 
[115] 
Schirrmann, T.; Krauss, J.; Arndt, M.A.; Rybak, S.M.; Dübel, S. Targeted therapeutic RNases (ImmunoRNases). Expert Opin. Biol. Ther.,  2009, 9(1), 79-95.
[http://dx.doi.org/10.1517/14712590802631862] [PMID:  19063695] 
[116] 
Jordaan, S.; Akinrinmade, O.A.; Nachreiner, T.; Cremer, C.; Naran, K.; Chetty, S.; Barth, S. Updates in the Development of ImmunoRNases for the Selective Killing of Tumor Cells. Biomedicines,  2018, 6(1), 6.
[http://dx.doi.org/10.3390/biomedicines6010028] [PMID:  29510557] 
[117] 
Lee, J.E.; Raines, R.T. Ribonucleases as novel chemotherapeutics: The ranpirnase example. BioDrugs,  2008, 22(1), 53-58.
[http://dx.doi.org/10.2165/00063030-200822010-00006] [PMID:  18215091] 
[118] 
Costanzi, J.; Sidransky, D.; Navon, A.; Goldsweig, H. Ribonucleases as a novel pro-apoptotic anticancer strategy: Review of the preclinical and clinical data for ranpirnase. Cancer Invest.,  2005, 23(7), 643-650.
[http://dx.doi.org/10.1080/07357900500283143] [PMID:  16305992] 
[119] 
Kanwar, S.S.; Kumar, K. Ribonuclease as anticancer therapeutics. Enz Eng.,  2017, 6, 1.
[http://dx.doi.org/10.4172/2329-6674.1000162]] 
[120] 
Squiquera, L.; Taxman, D.J.; Brendle, S.A.; Torres, R.; Sulley, J.; Hodge, T.; Christensen, N.; Sidransky, D. Ranpirnase eradicates human papillomavirus in cultured cells and heals anogenital warts in a Phase I study. Antivir. Ther.,  2017, 22(3), 247-255.
[http://dx.doi.org/10.3851/IMP3133] [PMID:  28121292] 
[121] 
Saxena, S.K.; Gravell, M.; Wu, Y-N.; Mikulski, S.M.; Shogen, K.; Ardelt, W.; Youle, R.J. Inhibition of HIV-1 production and selective degradation of viral RNA by an amphibian ribonuclease. J. Biol. Chem.,  1996, 271(34), 20783-20788.
[http://dx.doi.org/10.1074/jbc.271.34.20783] [PMID:  8702832] 
[122] 
Brand, R.M.; Siegel, A.; Myerski, A.; Metter, E.J.; Engstrom, J.; Brand, R.E.; Squiquera, L.; Hodge, T.; Sulley, J.; Cranston, R.D.; McGowan, I. Ranpirnase Reduces HIV-1 Infection and Associated Inflammatory Changes in a Human Colorectal Explant Model. AIDS Res. Hum. Retroviruses,  2018, 34(10), 838-848.
[http://dx.doi.org/10.1089/aid.2017.0308] [PMID:  29936861] 
[123] 
Hodge, T.; Draper, K.; Brasel, T.; Freiberg, A.; Squiquera, L.; Sidransky, D.; Sulley, J.; Taxman, D.J. Antiviral effect of ranpirnase against Ebola virus. Antiviral Res.,  2016, 132, 210-218.
[http://dx.doi.org/10.1016/j.antiviral.2016.06.009] [PMID:  27350309] 
[124] 
Hauge, A.; Rofstad, E.K. Antifibrotic therapy to normalize the tumor microenvironment. J. Transl. Med.,  2020, 18(1), 207.
[http://dx.doi.org/10.1186/s12967-020-02376-y] [PMID:  32434573] 
[125] 
Kultti, A.; Li, X.; Jiang, P.; Thompson, C.B.; Frost, G.I.; Shepard, H.M. Therapeutic targeting of hyaluronan in the tumor stroma. Cancers (Basel),  2012, 4(3), 873-903.
[http://dx.doi.org/10.3390/cancers4030873] [PMID:  24213471] 
[126] 
Auvinen, P.; Tammi, R.; Parkkinen, J.; Tammi, M.; Ågren, U.; Johansson, R.; Hirvikoski, P.; Eskelinen, M.; Kosma, V-M. Hyaluronan in peritumoral stroma and malignant cells associates with breast cancer spreading and predicts survival. Am. J. Pathol.,  2000, 156.
[127] 
Theocharis, A.D.; Skandalis, S.S.; Tzanakakis, G.N.; Karamanos, N.K. Proteoglycans in health and disease: Novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J.,  2010, 277(19), 3904-3923.
[http://dx.doi.org/10.1111/j.1742-4658.2010.07800.x] [PMID:  20840587] 
[128] 
Provenzano, P.P.; Cuevas, C.; Chang, A.E.; Goel, V.K.; Von Hoff, D.D.; Hingorani, S.R. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell,  2012, 21.
[129] 
Grass, G.D.; Dai, L.; Qin, Z.; Parsons, C.; Toole, B.P. CD147: Regulator of hyaluronan signaling in invasiveness and chemoresistance. Adv. Cancer Res.,  2014, 123, 351-373.
[http://dx.doi.org/10.1016/B978-0-12-800092-2.00013-7] [PMID:  25081536] 
[130] 
Shepard, H.M. Breaching the castle walls: hyaluronan depletion as a therapeutic approach to cancer therapy. Front. Oncol.,  2015, 5, 192.
[http://dx.doi.org/10.3389/fonc.2015.00192] [PMID:  26380222] 
[131] 
de Lemos, M.L.; Dar Santos, A. Clinical considerations of hyaluronidase as an adjunct to subcutaneous rituximab injection. J. Oncol. Pharm. Pract.,  2019, 25(4), 964-965.
[http://dx.doi.org/10.1177/1078155218817819] [PMID:  30975068] 
[132] 
Duco, M.R.; Murdock, J.L.; Reeves, D.J. Trastuzumab/hyaluronidase-oysk: a new option for patients with HER2-positive breast cancer. Ann. Pharmacother.,  2020, 54(3), 254-261.
[http://dx.doi.org/10.1177/1060028019877936] [PMID:  31595774] 
[133] 
Heo, Y-A.; Syed, Y.Y. Subcutaneous trastuzumab: a review in HER2-positive breast cancer. Target. Oncol.,  2019, 14(6), 749-758.
[http://dx.doi.org/10.1007/s11523-019-00684-y] [PMID:  31686307] 
[134] 
Gao, J.J.; Osgood, C.L.; Gong, Y.; Zhang, H.; Bloomquist, E.W.; Jiang, X.; Qiu, J.; Yu, J.; Song, P.; Rahman, A.; Chiu, H-J.; Ricks, T.K.; Rizvi, F.; Hou, S.; Wilson, W.; Abukhdeir, A.M.; Seidman, J.; Ghosh, S.; Philip, R.; Pierce, W.F.; Bhatnagar, V.; Kluetz, P.G.; Pazdur, R.; Beaver, J.A.; Amiri-Kordestani, L. FDA approval summary: pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use in patients with HER2-positive breast cancer. Clin. Cancer Res., 2020.
[http://dx.doi.org/10.1158/1078-0432.CCR-20-3474] [PMID:  33188141] 
[135] 
Lamb, Y.N. Daratumumab: a review in combination therapy for transplant-eligible newly diagnosed multiple myeloma. Drugs,  2020, 80(14), 1455-1464.
[http://dx.doi.org/10.1007/s40265-020-01385-x] [PMID:  32936436] 
[136] 
Maneval, D.C.; Caster, L.; Derunes, C.; Locke, K.W.; Muhsin, M.; Sauter, S.; Sekulovich, R.E.; Thompson, C.B.; LaBarre, M.J. Pegvorhyaluronidase alfa: A PEGylated recombinant human hyaluronidase PH20 for the treatment of cancers that accumulate hyaluronan; Polymer-Protein Conjugates, 2020, pp. 175-204.
[137] 
Infante, J.R.; Korn, R.L.; Rosen, L.S.; LoRusso, P.; Dychter, S.S.; Zhu, J.; Maneval, D.C.; Jiang, P.; Shepard, H.M.; Frost, G.; Von Hoff, D.D.; Borad, M.J.; Ramanathan, R.K. Phase 1 trials of PEGylated recombinant human hyaluronidase PH20 in patients with advanced solid tumours. Br. J. Cancer,  2018, 118.
[138] 
Hingorani, S.R.; Zheng, L.; Bullock, A.J.; Seery, T.E.; Harris, W.P.; Sigal, D.S.; Braiteh, F.; Ritch, P.S.; Zalupski, M.M.; Bahary, N.; Oberstein, P.E.; Wang-Gillam, A.; Wu, W.; Chondros, D.; Jiang, P.; Khelifa, S.; Pu, J.; Aldrich, C.; Hendifar, A.E. HALO 202: Randomized Phase II Study of PEGPH20 Plus Nab-Paclitaxel/Gemcitabine Versus Nab-Paclitaxel/Gemcitabine in Patients With Untreated, Metastatic Pancreatic Ductal Adenocarcinoma. J. Clin. Oncol.,  2018, 36(4), 359-366.
[http://dx.doi.org/10.1200/JCO.2017.74.9564] [PMID:  29232172] 
[139] 
Doherty, G.J.; Tempero, M.; Corrie, P.G. HALO-109-301: A Phase III trial of PEGPH20 (with gemcitabine and nab-paclitaxel) in hyaluronic acid-high stage IV pancreatic cancer. Future Oncol.,  2018, 14(1), 13-22.
[http://dx.doi.org/10.2217/fon-2017-0338] [PMID:  29235360] 
[140] 
Wong, K.M.; Horton, K.J.; Coveler, A.L.; Hingorani, S.R.; Harris, W.P. Targeting the Tumor Stroma: The Biology and Clinical Development of Pegylated Recombinant Human Hyaluronidase (PEGPH20). Curr. Oncol. Rep.,  2017, 19(7), 47.
[http://dx.doi.org/10.1007/s11912-017-0608-3] [PMID:  28589527] 
[141] 
Soundararajan, R.; Wang, G.; Petkova, A.; Uchegbu, I.F.; Schätzlein, A.G. Hyaluronidase coated molecular envelope technology nanoparticles enhance drug absorption via the subcutaneous route. Mol. Pharm.,  2020, 17(7), 2599-2611.
[http://dx.doi.org/10.1021/acs.molpharmaceut.0c00294] [PMID:  32379457] 
[142] 
Scodeller, P.; Catalano, P.N.; Salguero, N.; Duran, H.; Wolosiuk, A.; Soler-Illia, G.J.A.A. Hyaluronan degrading silica nanoparticles for skin cancer therapy. Nanoscale,  2013, 5(20), 9690-9698.
[http://dx.doi.org/10.1039/c3nr02787b] [PMID:  23969526] 
[143] 
Zhou, H.; Fan, Z.; Deng, J.; Lemons, P.K.; Arhontoulis, D.C.; Bowne, W.B.; Cheng, H. Hyaluronidase embedded in nanocarrier PEG shell for enhanced tumor penetration and highly efficient antitumor efficacy. Nano Lett.,  2016, 16(5), 3268-3277.
[http://dx.doi.org/10.1021/acs.nanolett.6b00820] [PMID:  27057591] 
[144] 
Zhou, H.; Fan, Z.; Lemons, P.K.; Cheng, H. A facile approach to functionalize cell membrane-coated nanoparticles. Theranostics,  2016, 6(7), 1012-1022.
[http://dx.doi.org/10.7150/thno.15095] [PMID:  27217834] 
[145] 
Kim, S.S.; Kim, H.K.; Kim, H.; Lee, W.T.; Lee, E.S.; Oh, K.T.; Choi, H-G.; Youn, Y.S. Hyperthermal paclitaxel-bound albumin nanoparticles co-loaded with indocyanine green and hyaluronidase for treating pancreatic cancers. Arch. Pharm. Res., 2020.
[http://dx.doi.org/10.1007/s12272-020-01264-9] [PMID:  32803685] 
[146] 
Dai, J.; Han, S.; Ju, F.; Han, M.; Xu, L.; Zhang, R.; Sun, Y. Preparation and evaluation of tumour microenvironment response multistage nanoparticles for epirubicin delivery and deep tumour penetration.Artif. Cells Nanomed. Biotechnol.,,  2018, 46(sup2), 860-873.
[http://dx.doi.org/10.1080/21691401.2018.1470528] [PMID: 29771149] 
[147] 
Yeldandi, A.V.; Yeldandi, V.; Kumar, S.; Murthy, C.V.; Wang, X.D.; Alvares, K.; Rao, M.S.; Reddy, J.K. Molecular evolution of the urate oxidase-encoding gene in hominoid primates: Nonsense mutations. Gene,  1991, 109(2), 281-284.
[http://dx.doi.org/10.1016/0378-1119(91)90622-I] [PMID:  1765273] 
[148] 
Alakel, N.; Middeke, J.M.; Schetelig, J.; Bornhäuser, M. Prevention and treatment of tumor lysis syndrome, and the efficacy and role of rasburicase. OncoTargets Ther.,  2017, 10, 597-605.
[http://dx.doi.org/10.2147/OTT.S103864] [PMID:  28203093] 
[149] 
Bayol, A.; Capdevielle, J.; Malazzi, P.; Buzy, A.; Claude Bonnet, M.; Colloc’h, N.; Mornon, J-P.; Loyaux, D.; Ferrara, P. Modification of a reactive cysteine explains differences between rasburicase and Uricozyme, a natural Aspergillus flavus uricase. Biotechnol. Appl. Biochem.,  2002, 36(1), 21-31.
[http://dx.doi.org/10.1042/BA20010083] [PMID:  12149119] 
[150] 
Owens, R.E.; Swanson, H.; Twilla, J.D. Hemolytic anemia induced by pegloticase infusion in a patient with G6PD deficiency.JCR: Journal of Clinical Rheumatology,  2016, 22
[151] 
Pui, C-H.; Mahmoud, H.H.; Wiley, J.M.; Woods, G.M.; Leverger, G.; Camitta, B.; Hastings, C.; Blaney, S.M.; Relling, M.V.; Reaman, G.H. Recombinant urate oxidase for the prophylaxis or treatment of hyperuricemia in patients With leukemia or lymphoma. J. Clin. Oncol.,  2001, 19(3), 697-704.
[http://dx.doi.org/10.1200/JCO.2001.19.3.697] [PMID:  11157020] 
[152] 
Sherman, M.R.; Saifer, M.G.P.; Perez-Ruiz, F. PEG-uricase in the management of treatment-resistant gout and hyperuricemia. Adv. Drug Deliv. Rev.,  2008, 60(1), 59-68.
[http://dx.doi.org/10.1016/j.addr.2007.06.011] [PMID:  17826865] 
[153] 
Hershfield, M.S.; Roberts, L.J.; Ganson, N.J.; Kelly, S.J.; Santisteban, I.; Scarlett, E.; Jaggers, D.; Sundy, J.S. Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc. Natl. Acad. Sci.,  2010, 107.
[http://dx.doi.org/10.1073/pnas.1001072107] 
[154] 
Schlesinger, N.; Lipsky, P.E. Pegloticase treatment of chronic refractory gout: Update on efficacy and safety. Semin. Arthritis Rheum.,  2020, 50(3S), S31-S38.
[http://dx.doi.org/10.1016/j.semarthrit.2020.04.011] [PMID:  32620200] 
[155] 
Najjari, A.; Rahimi, H.; Nojoumi, S.A.; Omidinia, E. Computational approach for rational design of fusion uricase with PAS sequences. Int. J. Mol. Cell. Med.,  2020, 9(1), 90-103.
[PMID:  32832488] 
[156] 
Geraths, C.; Daoud-El Baba, M.; Charpin-El Hamri, G.; Weber, W. A biohybrid hydrogel for the urate-responsive release of urate oxidase. J. Control. Release,  2013, 171(1), 57-62.
[http://dx.doi.org/10.1016/j.jconrel.2013.06.037] [PMID:  23838153] 
[157] 
Xiong, H.; Zhou, Y.; Zhou, Q.; He, D.; Wan, S.; Tan, Q.; Zhang, M.; Deng, X.; Zhang, J. Nanosomal microassemblies for highly efficient and safe delivery of therapeutic enzymes. ACS Appl. Mater. Interfaces,  2015, 7(36), 20255-20263.
[http://dx.doi.org/10.1021/acsami.5b05758] [PMID:  26325262] 
[158] 
Yoshimoto, M.; Takaki, N.; Yamasaki, M. Catalase-conjugated liposomes encapsulating glucose oxidase for controlled oxidation of glucose with decomposition of hydrogen peroxide produced. Colloids Surf. B Biointerfaces,  2010, 79(2), 403-408.
[http://dx.doi.org/10.1016/j.colsurfb.2010.05.006] [PMID:  20537512] 
[159] 
Zhou, Y.; Zhang, M.; He, D.; Hu, X.; Xiong, H.; Wu, J.; Zhu, B.; Zhang, J. Uricase alkaline enzymosomes with enhanced stabilities and anti-hyperuricemia effects induced by favorable microenvironmental changes. Sci. Rep.,  2016, 7, 20136.
[http://dx.doi.org/10.1038/srep20136] [PMID:  26823332] 
[160] 
Jung, S.; Kwon, I. Synergistic degradation of a hyperuricemia-causing metabolite using one-pot enzyme-nanozyme cascade reactions. Sci. Rep.,  2017, 7, 44330.
[http://dx.doi.org/10.1038/srep44330] [PMID:  28287162] 
[161] 
Kim, S.; Kim, M.; Jung, S.; Kwon, K.; Park, J.; Kim, S.; Kwon, I.; Tae, G. Co-delivery of therapeutic protein and catalase-mimic nanoparticle using a biocompatible nanocarrier for enhanced therapeutic effect. J. Control. Release,  2019, 309, 181-189.
[http://dx.doi.org/10.1016/j.jconrel.2019.07.038] [PMID:  31356840] 
[162] 
Minton, N.P.; Atkinson, T.; Sherwood, R.F. Molecular cloning of the Pseudomonas carboxypeptidase G2 gene and its expression in Escherichia coli and Pseudomonas putida. J. Bacteriol.,  1983, 156(3), 1222-1227.
[http://dx.doi.org/10.1128/jb.156.3.1222-1227.1983] [PMID:  6358192] 
[163] 
McCullough, J.L.; Chabner, B.A.; Bertino, J.R. Purification and properties of carboxypeptidase G 1. J. Biol. Chem.,  1971, 246(23), 7207-7213.
[http://dx.doi.org/10.1016/S0021-9258(19)45873-0] [PMID:  5129727] 
[164] 
Sherwood, R.F.; Melton, R.G.; Alwan, S.M.; Hughes, P. Purification and properties of carboxypeptidase G2 from Pseudomonas sp. strain RS-16. Use of a novel triazine dye affinity method. Eur. J. Biochem.,  1985, 148(3), 447-453.
[http://dx.doi.org/10.1111/j.1432-1033.1985.tb08860.x] [PMID:  3838935] 
[165] 
Rowsell, S.; Pauptit, R.A.; Tucker, A.D.; Melton, R.G.; Blow, D.M.; Brick, P. Crystal structure of carboxypeptidase G2, a bacterial enzyme with applications in cancer therapy. Structure,  1997, 5(3), 337-347.
[http://dx.doi.org/10.1016/S0969-2126(97)00191-3] [PMID:  9083113] 
[166] 
Green, J.M. Glucarpidase to combat toxic levels of methotrexate in patients. Ther. Clin. Risk Manag.,  2012, 8, 403-413.
[http://dx.doi.org/10.2147/TCRM.S30135] [PMID:  23209370] 
[167] 
Al-Qahtani, A.D.; Bashraheel, S.S.; Rashidi, F.B.; O’Connor, C.D.; Romero, A.R.; Domling, A.; Goda, S.K. Production of “biobetter” variants of glucarpidase with enhanced enzyme activity. Biomed. Pharmacother.,  2019, 112(108725)108725
[http://dx.doi.org/10.1016/j.biopha.2019.108725] [PMID:  30970523] 
[168] 
Available from. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2012/125327lbl.pdf
[169] 
Bedoui, Y.; Guillot, X.; Sélambarom, J.; Guiraud, P.; Giry, C.; Jaffar-Bandjee, M.C.; Ralandison, S.; Gasque, P. Methotrexate an Old Drug with New Tricks. Int. J. Mol. Sci.,  2019, 20(20)E5023
[http://dx.doi.org/10.3390/ijms20205023] [PMID:  31658782] 
[170] 
Widemann, B.C.; Adamson, P.C. Understanding and managing methotrexate nephrotoxicity. Oncologist,  2006, 11(6), 694-703.
[http://dx.doi.org/10.1634/theoncologist.11-6-694] [PMID:  16794248] 
[171] 
Hansen, H.H.; Selawry, O.S.; Holland, J.F.; McCall, C.B. The variability of individual tolerance to methotrexate in cancer patients. Br. J. Cancer,  1971, 25(2), 298-305.
[http://dx.doi.org/10.1038/bjc.1971.38] [PMID:  4256007] 
[172] 
Buchen, S.; Ngampolo, D.; Melton, R.G.; Hasan, C.; Zoubek, A.; Henze, G.; Bode, U.; Fleischhack, G. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br. J. Cancer,  2005, 92(3), 480-487.
[http://dx.doi.org/10.1038/sj.bjc.6602337] [PMID:  15668713] 
[173] 
Tuffaha, H.W.; Al Omar, S. Glucarpidase for the treatment of life-threatening methotrexate overdose. Drugs Today (Barc),  2012, 48(11), 705-711.
[http://dx.doi.org/10.1358/dot.2012.48.11.1871575] [PMID:  23170306] 
[174] 
Available from. https://www.wepclinical.com/wep-clinical-partners-with-btg-specialty-pharmaceuticals-for-european-supply-of-voraxaze/
[175] 
Widemann, B.C.; Sung, E.; Anderson, L.; Salzer, W.L.; Balis, F.M.; Monitjo, K.S.; McCully, C.; Hawkins, M.; Adamson, P.C. Pharmacokinetics and metabolism of the methotrexate metabolite 2, 4-diamino-N(10)-methylpteroic acid. J. Pharmacol. Exp. Ther.,  2000, 294(3), 894-901.
[PMID:  10945838] 
[176] 
Schwartz, S.; Borner, K.; Müller, K.; Martus, P.; Fischer, L.; Korfel, A.; Auton, T.; Thiel, E. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist,  2007, 12(11), 1299-1308.
[http://dx.doi.org/10.1634/theoncologist.12-11-1299] [PMID:  18055849] 
[177] 
Widemann, B.C.; Balis, F.M.; Kim, A.; Boron, M.; Jayaprakash, N.; Shalabi, A.; O’Brien, M.; Eby, M.; Cole, D.E.; Murphy, R.F.; Fox, E.; Ivy, P.; Adamson, P.C. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: Clinical and pharmacologic factors affecting outcome. J. Clin. Oncol.,  2010, 28(25), 3979-3986.
[http://dx.doi.org/10.1200/JCO.2009.25.4540] [PMID:  20679598] 
[178] 
Widemann, B.C.; Balis, F.M.; Shalabi, A.; Boron, M.; O’Brien, M.; Cole, D.E.; Jayaprakash, N.; Ivy, P.; Castle, V.; Muraszko, K.; Moertel, C.L.; Trueworthy, R.; Hermann, R.C.; Moussa, A.; Hinton, S.; Reaman, G.; Poplack, D.; Adamson, P.C. Treatment of accidental intrathecal methotrexate overdose with intrathecal carboxypeptidase G2. J. Natl. Cancer Inst.,  2004, 96(20), 1557-1559.
[http://dx.doi.org/10.1093/jnci/djh270] [PMID:  15494606] 
[179] 
Available from. https://www.who.int/health-topics/cardiovascular-diseases
[180] 
Undas, A.; Ariëns, R.A.S. Fibrin clot structure and function: A role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler. Thromb. Vasc. Biol.,  2011, 31(12), e88-e99.
[http://dx.doi.org/10.1161/ATVBAHA.111.230631] [PMID:  21836064] 
[181] 
Mosesson, M.W. Fibrinogen and fibrin structure and functions. J. Thromb. Haemost.,  2005, 3(8), 1894-1904.
[http://dx.doi.org/10.1111/j.1538-7836.2005.01365.x] [PMID:  16102057] 
[182] 
Chapin, J.C.; Hajjar, K.A. Fibrinolysis and the control of blood coagulation. Blood Rev.,  2015, 29(1), 17-24.
[http://dx.doi.org/10.1016/j.blre.2014.09.003] [PMID:  25294122] 
[183] 
Mican, J.; Toul, M.; Bednar, D.; Damborsky, J. Structural biology and protein engineering of thrombolytics. Comput. Struct. Biotechnol. J.,  2019, 17, 917-938.
[http://dx.doi.org/10.1016/j.csbj.2019.06.023] [PMID:  31360331] 
[184] 
Castellino, F.J.; Ploplis, V.A. Structure and function of the plasminogen/plasmin system. Thromb. Haemost.,  2005, 93(4), 647-654.
[http://dx.doi.org/10.1160/TH04-12-0842] [PMID:  15841308] 
[185] 
Law, R.H.P.; Caradoc-Davies, T.; Cowieson, N.; Horvath, A.J.; Quek, A.J.; Encarnacao, J.A.; Steer, D.; Cowan, A.; Zhang, Q.; Lu, B.G.C.; Pike, R.N.; Smith, A.I.; Coughlin, P.B.; Whisstock, J.C. The X-ray crystal structure of full-length human plasminogen. Cell Rep.,  2012, 1(3), 185-190.
[http://dx.doi.org/10.1016/j.celrep.2012.02.012] [PMID:  22832192] 
[186] 
Law, R.H.P.; Abu-Ssaydeh, D.; Whisstock, J.C. New insights into the structure and function of the plasminogen/plasmin system. Curr. Opin. Struct. Biol.,  2013, 23(6), 836-841.
[http://dx.doi.org/10.1016/j.sbi.2013.10.006] [PMID:  24252474] 
[187] 
Irigoyen, J.P.; Muñoz-Cánoves, P.; Montero, L.; Koziczak, M.; Nagamine, Y. The plasminogen activator system: Biology and regulation. Cell. Mol. Life Sci.,  1999, 56(1-2), 104-132.
[http://dx.doi.org/10.1007/PL00000615] [PMID:  11213252] 
[188] 
Urano, T.; Castellino, F.J.; Suzuki, Y. Regulation of plasminogen activation on cell surfaces and fibrin. J. Thromb. Haemost.,  2018, 16(8), 1487-1497.
[http://dx.doi.org/10.1111/jth.14157] [PMID:  29779246] 
[189] 
Kotb, E. Activity assessment of microbial fibrinolytic enzymes. Appl. Microbiol. Biotechnol.,  2013, 97(15), 6647-6665.
[http://dx.doi.org/10.1007/s00253-013-5052-1] [PMID:  23812278] 
[190] 
Kumar, S.S.; Sabu, A. Therapeutic Enzymes: Function and Clinical Implications; Labrou, N., Ed.; , 2019, Vol. 1148, pp. 345-381.
[http://dx.doi.org/10.1007/978-981-13-7709-9_15] 
[191] 
Nihalani, D.; Sahni, G. Streptokinase contains two independent plasminogen-binding sites. Biochem. Biophys. Res. Commun.,  1995, 217(3), 1245-1254.
[http://dx.doi.org/10.1006/bbrc.1995.2902] [PMID:  8554583] 
[192] 
Banerjee, A.; Chisti, Y.; Banerjee, U.C. Streptokinase--a clinically useful thrombolytic agent. Biotechnol. Adv.,  2004, 22(4), 287-307.
[http://dx.doi.org/10.1016/j.biotechadv.2003.09.004] [PMID:  14697452] 
[193] 
Reed, G.L.; Houng, A.K.; Liu, L.; Parhami-Seren, B.; Matsueda, L.H.; Wang, S.; Hedstrom, L. A catalytic switch and the conversion of streptokinase to a fibrin-targeted plasminogen activator. Proc. Natl. Acad. Sci. USA,  1999, 96(16), 8879-8883.
[http://dx.doi.org/10.1073/pnas.96.16.8879] [PMID:  10430864] 
[194] 
Sazonova, I.Y.; Robinson, B.R.; Gladysheva, I.P.; Castellino, F.J.; Reed, G.L. Alpha Domain deletion converts streptokinase into a fibrin-dependent plasminogen activator through mechanisms akin to staphylokinase and tissue plasminogen activator. J. Biol. Chem.,  2004, 279(24), 24994-25001.
[http://dx.doi.org/10.1074/jbc.M400253200] [PMID:  15069059] 
[195] 
Kazmi, K.A.; Perwaiz Iqbal, M.; Rahbar, A.; Mehboobali, N. Anti-streptokinase titers and response to streptokinase treatment in Pakistani patients. Int. J. Cardiol.,  2002, 82(3), 247-251.
[http://dx.doi.org/10.1016/S0167-5273(02)00004-9] [PMID:  11911912] 
[196] 
Sikri, N.; Bardia, A. A history of streptokinase use in acute myocardial infarction. Tex. Heart Inst. J.,  2007, 34(3), 318-327.
[PMID:  17948083] 
[197] 
(GISSI), G.I.p.l.S.d.S.n.I.M., Long-term effects of intravenous thrombolysis in acute myocardial infarction: Final report of the GISSI study. Lancet,  1987, 2, 871-874.
[198] 
Available from. https://www.medicines.org.uk/emc/product/4255/smpc
[199] 
Available from. https://www.medicines.org.uk/emc/product/4256/smpc
[200] 
Available from. www.medicines.org.uk/emc/product/264/smpc
[201] 
Available from. https://www.medicines.org.uk/emc/product/898/smpc
[202] 
Available from. https://www.medicines.org.uk/emc/product/3013/smpc
[203] 
Chester, K.W.; Corrigan, M.; Schoeffler, J.M.; Shah, M.; Toy, F.; Purdon, B.; Dillon, G.M. Making a case for the right '-ase’ in acute ischemic stroke: Alteplase, tenecteplase, and reteplase. Expert Opin. Drug Saf.,  2019, 18(2), 87-96.
[http://dx.doi.org/10.1080/14740338.2019.1573985] [PMID:  30712409] 
[204] 
Smith, R.A.G.; Dupe, R.J.; English, P.D.; Green, J. Fibrinolysis with acyl-enzymes: A new approach to thrombolytic therapy. Nature,  1981, 290(5806), 505-508.
[http://dx.doi.org/10.1038/290505a0] [PMID:  7219537] 
[205] 
Sherry, S. Pharmacology of anistreplase. Clin. Cardiol.,  1990, 13(3)(Suppl. 5), V3-V10.
[http://dx.doi.org/10.1002/clc.4960131303] [PMID:  2182238] 
[206] 
Adivitiya; Khasa, Y.P. The evolution of recombinant thrombolytics: Current status and future directions. Bioengineered,  2017, 8(4), 331-358.
[http://dx.doi.org/10.1080/21655979.2016.1229718] [PMID:  27696935] 
[207] 
MacFarlane, R.G.; Pilling, J. Fibrinolytic activity of normal urine. Nature,  1947, 159(4049), 779.
[http://dx.doi.org/10.1038/159779a0] [PMID:  20241608] 
[208] 
Crippa, M.P. Urokinase-type plasminogen activator. Int. J. Biochem. Cell Biol.,  2007, 39(4), 690-694.
[http://dx.doi.org/10.1016/j.biocel.2006.10.008] [PMID:  17118695] 
[209] 
Blasi, F.; Carmeliet, P. uPAR: A versatile signalling orchestrator. Nat. Rev. Mol. Cell Biol.,  2002, 3(12), 932-943.
[http://dx.doi.org/10.1038/nrm977] [PMID:  12461559] 
[210] 
Appella, E.; Blasi, F. The growth factor module of urokinase is the binding sequence for its receptor. Ann. N. Y. Acad. Sci.,  1987, 511, 192-195.
[http://dx.doi.org/10.1111/j.1749-6632.1987.tb36247.x] [PMID:  2830824] 
[211] 
Conese, M.; Blasi, F. Urokinase/urokinase receptor system: Internalization/degradation of urokinase-serpin complexes: Mechanism and regulation. Biol. Chem. Hoppe Seyler,  1995, 376(3), 143-155.
[PMID:  7612191] 
[212] 
Gurewich, V. Fibrinolysis: a misunderstood natural defense whose therapeutic potential is unknown. Cardiovasc. Drugs Ther.,  2019, 33(6), 749-753.
[http://dx.doi.org/10.1007/s10557-019-06923-8] [PMID:  31897763] 
[213] 
Kadir, R.R.A.; Bayraktutan, U. Urokinase plasminogen activator: a potential thrombolytic agent for ischaemic stroke. Cell. Mol. Neurobiol.,  2020, 40(3), 347-355.
[http://dx.doi.org/10.1007/s10571-019-00737-w] [PMID:  31552559] 
[214] 
Astrup, T.; Permin, P.M. Fibrinolysis in the animal organism. Nature,  1947, 159(4046), 681-682.
[http://dx.doi.org/10.1038/159681b0] [PMID:  20342264] 
[215] 
Astrup, T.; Stage, A. Isolation of a soluble fibrinolytic activator from animal tissue. Nature,  1952, 170(4335), 929.
[http://dx.doi.org/10.1038/170929a0] [PMID:  13013265] 
[216] 
Collen, D.; Lijnen, H.R. The tissue-type plasminogen activator story. Arterioscler. Thromb. Vasc. Biol.,  2009, 29(8), 1151-1155.
[http://dx.doi.org/10.1161/ATVBAHA.108.179655] [PMID:  19605778] 
[217] 
Larsen, G.R.; Metzger, M.; Henson, K.; Blue, Y.; Horgan, P. Pharmacokinetic and distribution analysis of variant forms of tissue-type plasminogen activator with prolonged clearance in rat. Blood,  1989, 73(7), 1842-1850.
[http://dx.doi.org/10.1182/blood.V73.7.1842.1842] [PMID:  2496774] 
[218] 
Narita, M.; Bu, G.; Herz, J.; Schwartz, A.L. Two receptor systems are involved in the plasma clearance of tissue-type plasminogen activator (t-PA) in vivo. J. Clin. Invest.,  1995, 96(2), 1164-1168.
[http://dx.doi.org/10.1172/JCI118105] [PMID:  7635954] 
[219] 
Lijnen, H.R.; Collen, D. Strategies for the improvement of thrombolytic agents. Thromb. Haemost.,  1991, 66(1), 88-110.
[http://dx.doi.org/10.1055/s-0038-1646377] [PMID:  1926054] 
[220] 
Pennica, D.; Holmes, W.E.; Kohr, W.J.; Harkins, R.N.; Vehar, G.A.; Ward, C.A.; Bennett, W.F.; Yelverton, E.; Seeburg, P.H.; Heyneker, H.L.; Goeddel, D.V.; Collen, D. Cloning and expression of human tissue-type plasminogen activator cDNA in E. coli. Nature,  1983, 301(5897), 214-221.
[http://dx.doi.org/10.1038/301214a0] [PMID:  6337343] 
[221] 
Hacke, W.; Kaste, M.; Bluhmki, E.; Brozman, M.; Dávalos, A.; Guidetti, D.; Larrue, V.; Lees, K.R.; Medeghri, Z.; Machnig, T.; Schneider, D.; von Kummer, R.; Wahlgren, N.; Toni, D.; Investigators, E. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N. Engl. J. Med.,  2008, 359(13), 1317-1329.
[http://dx.doi.org/10.1056/NEJMoa0804656] [PMID:  18815396] 
[222] 
Leung, T.W.H.; Wong, K.S.L. Thrombolysis with alteplase for acute ischemic stroke: Safe and effective outside the 3-hour time window? Nat. Clin. Pract. Neurol.,  2009, 5(2), 70-71.
[http://dx.doi.org/10.1038/ncpneuro0993] [PMID:  19107108] 
[223] 
Choudhury, R.; Barrett, C.D.; Moore, H.B.; Moore, E.E.; McIntyre, R.C.; Moore, P.K.; Talmor, D.S.; Nydam, T.L.; Yaffe, M.B. Salvage use of tissue plasminogen activator (tPA) in the setting of acute respiratory distress syndrome (ARDS) due to COVID-19 in the USA: A Markov decision analysis. World J. Emerg. Surg.,  2020, 15(1), 29.
[http://dx.doi.org/10.1186/s13017-020-00305-4] [PMID:  32312290] 
[224] 
Dobesh, P.P.; Trujillo, T.C. Coagulopathy, Venous Thromboembolism, and Anticoagulation in Patients with COVID-19. Pharmacotherapy,  2020, 40(11), 1130-1151.
[http://dx.doi.org/10.1002/phar.2465] [PMID:  33006163] 
[225] 
Kollias, A.; Kyriakoulis, K.G.; Dimakakos, E.; Poulakou, G.; Stergiou, G.S.; Syrigos, K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: Emerging evidence and call for action. Br. J. Haematol.,  2020, 189(5), 846-847.
[http://dx.doi.org/10.1111/bjh.16727] [PMID:  32304577] 
[226] 
Paranjpe, I.; Fuster, V.; Lala, A.; Russak, A.J.; Glicksberg, B.S.; Levin, M.A.; Charney, A.W.; Narula, J.; Fayad, Z.A.; Bagiella, E.; Zhao, S.; Nadkarni, G.N. Association of Treatment Dose Anticoagulation With In-Hospital Survival Among Hospitalized Patients With COVID-19. J. Am. Coll. Cardiol.,  2020, 76(1), 122-124.
[http://dx.doi.org/10.1016/j.jacc.2020.05.001] [PMID:  32387623] 
[227] 
Horie, S.; McNicholas, B.; Rezoagli, E.; Pham, T.; Curley, G.; McAuley, D.; O’Kane, C.; Nichol, A.; Dos Santos, C.; Rocco, P.R.M.; Bellani, G.; Laffey, J.G. Emerging pharmacological therapies for ARDS: COVID-19 and beyond. Intensive Care Med.,  2020, 46(12), 2265-2283.
[http://dx.doi.org/10.1007/s00134-020-06141-z] [PMID:  32654006] 
[228] 
Ranucci, M.; Sitzia, C.; Baryshnikova, E.; Di Dedda, U.; Cardani, R.; Martelli, F.; Corsi Romanelli, M. Covid-19-associated coagulopathy: biomarkers of thrombin generation and fibrinolysis leading the outcome. J. Clin. Med.,  2020, 9(11)E3487
[http://dx.doi.org/10.3390/jcm9113487] [PMID:  33126772] 
[229] 
Zhou, F.; Yu, T.; Du, R.; Fan, G.; Liu, Y.; Liu, Z.; Xiang, J.; Wang, Y.; Song, B.; Gu, X.; Guan, L.; Wei, Y.; Li, H.; Wu, X.; Xu, J.; Tu, S.; Zhang, Y.; Chen, H.; Cao, B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: A retrospective cohort study. Lancet,  2020, 395(10229), 1054-1062.
[http://dx.doi.org/10.1016/S0140-6736(20)30566-3] [PMID:  32171076] 
[230] 
Bikdeli, B.; Madhavan, M.V.; Gupta, A.; Jimenez, D.; Burton, J.R.; Der Nigoghossian, C.; Chuich, T.; Nouri, S.N.; Dreyfus, I.; Driggin, E.; Sethi, S.; Sehgal, K.; Chatterjee, S.; Ageno, W.; Madjid, M.; Guo, Y.; Tang, L.V.; Hu, Y.; Bertoletti, L.; Giri, J.; Cushman, M.; Quéré, I.; Dimakakos, E.P.; Gibson, C.M.; Lippi, G.; Favaloro, E.J.; Fareed, J.; Tafur, A.J.; Francese, D.P.; Batra, J.; Falanga, A.; Clerkin, K.J.; Uriel, N.; Kirtane, A.; McLintock, C.; Hunt, B.J.; Spyropoulos, A.C.; Barnes, G.D.; Eikelboom, J.W.; Weinberg, I.; Schulman, S.; Carrier, M.; Piazza, G.; Beckman, J.A.; Leon, M.B.; Stone, G.W.; Rosenkranz, S.; Goldhaber, S.Z.; Parikh, S.A.; Monreal, M.; Krumholz, H.M.; Konstantinides, S.V.; Weitz, J.I.; Lip, G.Y.H.; Global, C-T.C. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb. Haemost.,  2020, 120(7), 1004-1024.
[http://dx.doi.org/10.1055/s-0040-1713152] [PMID:  32473596] 
[231] 
Moore, H.B.; Barrett, C.D.; Moore, E.E.; McIntyre, R.C.; Moore, P.K.; Talmor, D.S.; Moore, F.A.; Yaffe, M.B. Is there a role for tissue plasminogen activator as a novel treatment for refractory COVID-19 associated acute respiratory distress syndrome? J. Trauma Acute Care Surg.,  2020, 88(6), 713-714.
[http://dx.doi.org/10.1097/TA.0000000000002694] [PMID:  32281766] 
[232] 
Hardaway, R.M.; Harke, H.; Tyroch, A.H.; Williams, C.H.; Vazquez, Y.; Krause, G.F. Treatment of severe acute respiratory distress syndrome: A final report on a phase I study. Am. Surg.,  2001, 67(4), 377-382.
[PMID:  11308009] 
[233] 
Abdelaal Ahmed Mahmoud, A.; Mahmoud, H.E.; Mahran, M.A.; Khaled, M. Streptokinase Versus Unfractionated heparin nebulization in patients with severe acute respiratory distress syndrome (ARDS): a randomized controlled trial with observational controls. J. Cardiothorac. Vasc. Anesth.,  2020, 34(2), 436-443.
[http://dx.doi.org/10.1053/j.jvca.2019.05.035] [PMID:  31262641] 
[234] 
Goyal, A.; Saigal, S.; Niwariya, Y.; Sharma, J.; Singh, P. Successful use of tPA for thrombolysis in COVID related ARDS: A case series. J. Thromb. Thrombolysis, 2020.
[http://dx.doi.org/10.1007/s11239-020-02208-2] [PMID:  32617806] 
[235] 
Poor, H.D.; Ventetuolo, C.E.; Tolbert, T.; Chun, G.; Serrao, G.; Zeidman, A.; Dangayach, N.S.; Olin, J.; Kohli-Seth, R.; Powell, C.A. COVID-19 critical illness pathophysiology driven by diffuse pulmonary thrombi and pulmonary endothelial dysfunction responsive to thrombolysis. Clin. Transl. Med.,  2020, 10(2)e44
[http://dx.doi.org/10.1002/ctm2.44] [PMID:  32508062] 
[236] 
Wang, J.; Hajizadeh, N.; Moore, E.E.; McIntyre, R.C.; Moore, P.K.; Veress, L.A.; Yaffe, M.B.; Moore, H.B.; Barrett, C.D. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS): A case series. J. Thromb. Haemost.,  2020, 18(7), 1752-1755.
[http://dx.doi.org/10.1111/jth.14828] [PMID:  32267998] 
[237] 
Carneiro, T.; Dashkoff, J.; Leung, L.Y.; Nobleza, C.O.S.; Marulanda-Londono, E.; Hathidara, M.; Koch, S.; Sur, N.; Boske, A.; Voetsch, B.; Aboul Nour, H.; Miller, D.J.; Daneshmand, A.; Shulman, J.; Curiale, G.; Greer, D.M.; Romero, J.R.; Anand, P.; Cervantes-Arslanian, A.M. Intravenous tPA for Acute Ischemic Stroke in Patients with COVID-19. J. Stroke Cerebrovasc. Dis.,  2020, 29(11)105201
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2020.105201] [PMID:  33066885] 
[238] 
Keyt, B.A.; Paoni, N.F.; Refino, C.J.; Berleau, L.; Nguyen, H.; Chow, A.; Lai, J.; Peña, L.; Pater, C.; Ogez, J.; Etcheverry, T.; Botstein, D.; Bennett, W.F. A faster-acting and more potent form of tissue plasminogen activator. Proc. Natl. Acad. Sci. USA,  1994, 91(9), 3670-3674.
[http://dx.doi.org/10.1073/pnas.91.9.3670] [PMID:  8170967] 
[239] 
Cannon, C.P.; McCabe, C.H.; Gibson, C.M.; Ghali, M.; Sequeira, R.F.; McKendall, G.R.; Breed, J.; Modi, N.B.; Fox, N.L.; Tracy, R.P.; Love, T.W.; Braunwald, E.; Coulson, T.; Mayor, M.R.; Girwarr, G.; Teixeiro, P.; Williams, D.O.; McDonald, M.; Kirshenbaum, J.M.; Cloutier, J.; Henry, T.D.; Knox, L.; Boisjolie, C.; Schweiger, M.J.; Burkott, B.; Warwick, D.; Carney, R.; Murphy, G.; Cutler, D.; Malmberg, G.; Greene, R.M.; Healy, E.; Perry, V.; Watkins, M.; Sobel, B.E.; Rowen, M.; Wilson, W.; Cuttitta, J.; Niederman, A.; Kellerman, T.; Frey, M.; Taylor, H.; Mueller, H.S.; Kunkel, L.; Cosico, J.; Casale, P.; Tuzi, J.; Rogers, W.J.; Morgan, T.; Anderson, J.L.; Karagounis, L.; Allen, A.; Hochman, J.S.; McAnulty, M. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation,  1997, 95(2), 351-356.
[http://dx.doi.org/10.1161/01.CIR.95.2.351] [PMID:  9008448] 
[240] 
Zeymer, U.; Neuhaus, K.L. Clinical trials in acute myocardial infarction. Curr. Opin. Cardiol.,  1999, 14(5), 392-402.
[http://dx.doi.org/10.1097/00001573-199909000-00007] [PMID:  10500901] 
[241] 
Kohnert, U.; Rudolph, R.; Verheijen, J.H.; Weening-Verhoeff, E.J.D.; Stern, A.; Opitz, U.; Martin, U.; Lill, H.; Prinz, H.; Lechner, M.; Kresse, G.B.; Buckel, P.; Fischer, S. Biochemical properties of the kringle 2 and protease domains are maintained in the refolded t-PA deletion variant BM 06.022. Protein Eng.,  1992, 5(1), 93-100.
[http://dx.doi.org/10.1093/protein/5.1.93] [PMID:  1321420] 
[242] 
Malcolm, A.D.; Keltai, M.; Walsh, M.J.; Hennersdorf, G.; Dymond, D.; Fabian, J.; Sochman, J.; Bertrand, M.; Masquet, C.; Letac, B.; Bory, M.; Eha, J.; DeVita, C.; Ravazzi, P.; Gatto, E.; Abbadessa, F.; Perrins, J.; Walsh, M.; Daly, K. ESPRIT: A European study of the prevention of reocclusion after initial thrombolysis with duteplase in acute myocardial infarction. Eur. Heart J.,  1996, 17(10), 1522-1531.
[http://dx.doi.org/10.1093/oxfordjournals.eurheartj.a014716] [PMID:  8909909] 
[243] 
Martin, U.; von Möllendorff, E.; Akpan, W.; Kientsch-Engel, R.; Kaufmann, B.; Neugebauer, G. Pharmacokinetic and hemostatic properties of the recombinant plasminogen activator bm 06.022 in healthy volunteers. Thromb. Haemost.,  1991, 66(5), 569-574.
[http://dx.doi.org/10.1055/s-0038-1646461] [PMID:  1725068] 
[244] 
Oikawa, K.; Watanabe, T.; Higuchi, S. Comparison of drug disposition between wild-type and novel tissue-type plasminogen activator pamiteplase in rats. Drug Metab. Dispos.,  2000, 28(9), 1087-1093.
[PMID:  10950854] 
[245] 
Oikawa, K.; Watanabe, T.; Miyamoto, I.; Higuchi, S. Determination, pharmacokinetics and protein binding of a novel tissue-type plasminogen activator, pamiteplase in human plasma. Xenobiotica,  2000, 30(10), 993-1003.
[http://dx.doi.org/10.1080/00498250050200140] [PMID:  11315107] 
[246] 
Agnelli, G.; Pascucci, C.; Nenci, G.G.; Mele, A.; Bürgi, R.; Heim, J. Thrombolytic and haemorrhagic effects of bolus doses of tissue-type plasminogen activator and a hybrid plasminogen activator with prolonged plasma half-life (K2tu-PA: CGP 42935). Thromb. Haemost.,  1993, 70(2), 294-300.
[http://dx.doi.org/10.1055/s-0038-1649569] [PMID:  8236138] 
[247] 
Nedaeinia, R.; Faraji, H.; Javanmard, S.H.; Ferns, G.A.; Ghayour-Mobarhan, M.; Goli, M.; Mashkani, B.; Nedaeinia, M.; Haghighi, M.H.H.; Ranjbar, M. Bacterial staphylokinase as a promising third-generation drug in the treatment for vascular occlusion. Mol. Biol. Rep.,  2020, 47(1), 819-841.
[http://dx.doi.org/10.1007/s11033-019-05167-x] [PMID:  31677034] 
[248] 
Hawkey, C. Plasminogen activator in saliva of the vampire bat Desmodus rotundus. Nature,  1966, 211(5047), 434-435.
[http://dx.doi.org/10.1038/211434c0] [PMID:  5967844] 
[249] 
Krätzschmar, J.; Haendler, B.; Langer, G.; Boidol, W.; Bringmann, P.; Alagon, A.; Donner, P.; Schleuning, W.D. The plasminogen activator family from the salivary gland of the vampire bat Desmodus rotundus: Cloning and expression. Gene,  1991, 105(2), 229-237.
[http://dx.doi.org/10.1016/0378-1119(91)90155-5] [PMID:  1937019] 
[250] 
Schleuning, W.D.; Alagon, A.; Boidol, W.; Bringmann, P.; Petri, T.; Krätzschmar, J.; Haendler, B.; Langer, G.; Baldus, B.; Witt, W.; Donner, P. Plasminogen activators from the saliva of Desmodus rotundus (common vampire bat): Unique fibrin specificity. Ann. N. Y. Acad. Sci.,  1992, 667, 395-403.
[http://dx.doi.org/10.1111/j.1749-6632.1992.tb51639.x] [PMID:  1309059] 
[251] 
Bringmann, P.; Gruber, D.; Liese, A.; Toschi, L.; Krätzchmar, J.; Schleuning, W.D.; Donner, P. Structural features mediating fibrin selectivity of vampire bat plasminogen activators. J. Biol. Chem.,  1995, 270(43), 25596-25603.
[http://dx.doi.org/10.1074/jbc.270.43.25596] [PMID:  7592732] 
[252] 
Medcalf, R.L. Desmoteplase: Discovery, insights and opportunities for ischaemic stroke. Br. J. Pharmacol.,  2012, 165(1), 75-89.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01514.x] [PMID:  21627637] 
[253] 
Schleuning, W.D. Vampire bat plasminogen activator DSPA-alpha-1 (desmoteplase): A thrombolytic drug optimized by natural selection. Haemostasis,  2001, 31(3-6), 118-122.
[PMID:  11910176] 
[254] 
Hacke, W.; Furlan, A.J.; Al-Rawi, Y.; Davalos, A.; Fiebach, J.B.; Gruber, F.; Kaste, M.; Lipka, L.J.; Pedraza, S.; Ringleb, P.A.; Rowley, H.A.; Schneider, D.; Schwamm, L.H.; Leal, J.S.; Söhngen, M.; Teal, P.A.; Wilhelm-Ogunbiyi, K.; Wintermark, M.; Warach, S. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): A prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol.,  2009, 8(2), 141-150.
[http://dx.doi.org/10.1016/S1474-4422(08)70267-9] [PMID:  19097942] 
[255] 
von Kummer, R.; Mori, E.; Truelsen, T.; Jensen, J.S.; Grønning, B.A.; Fiebach, J.B.; Lovblad, K.O.; Pedraza, S.; Romero, J.M.; Chabriat, H.; Chang, K.C.; Dávalos, A.; Ford, G.A.; Grotta, J.; Kaste, M.; Schwamm, L.H.; Shuaib, A.; Albers, G.W.; Investigators, D. Desmoteplase 3 to 9 Hours After Major Artery Occlusion Stroke: The DIAS-4 Trial (Efficacy and Safety Study of Desmoteplase to Treat Acute Ischemic Stroke). Stroke,  2016, 47(12), 2880-2887.
[http://dx.doi.org/10.1161/STROKEAHA.116.013715] [PMID:  27803391] 
[256] 
Rabijns, A.; De Bondt, H.L.; De Ranter, C. Three-dimensional structure of staphylokinase, a plasminogen activator with therapeutic potential. Nat. Struct. Biol.,  1997, 4(5), 357-360.
[http://dx.doi.org/10.1038/nsb0597-357] [PMID:  9145104] 
[257] 
Marder, V.J.; Novokhatny, V. Direct fibrinolytic agents: Biochemical attributes, preclinical foundation and clinical potential. J. Thromb. Haemost.,  2010, 8(3), 433-444.
[http://dx.doi.org/10.1111/j.1538-7836.2009.03701.x] [PMID:  19943877] 
[258] 
Marder, V.J. Historical perspective and future direction of thrombolysis research: The re-discovery of plasmin. J. Thromb. Haemost.,  2011, 9(Suppl. 1), 364-373.
[http://dx.doi.org/10.1111/j.1538-7836.2011.04370.x] [PMID:  21781273] 
[259] 
Hoefer, I.E.; Stroes, E.S.G.; Pasterkamp, G.; Levi, M.M.; Reekers, J.A.; Verhagen, H.J.M.; Meijers, J.C.; Humphries, J.E.; Rotmans, J.I. Locally applied recombinant plasmin results in effective thrombolysis in a porcine model of arteriovenous graft thrombosis. J. Vasc. Interv. Radiol.,  2009, 20(7), 951-958.
[http://dx.doi.org/10.1016/j.jvir.2009.03.043] [PMID:  19481472] 
[260] 
Shlansky-Goldberg, R.D.; Matsumoto, A.H.; Baumbach, G.A.; Siegel, J.B.; Raabe, R.D.; Murphy, T.P.; Deng, C.; Ray Dawkins, J.; Marder, V.J. A first-in-human phase I trial of locally delivered human plasmin for hemodialysis graft occlusion. J. Thromb. Haemost.,  2008, 6(6), 944-950.
[http://dx.doi.org/10.1111/j.1538-7836.2008.02969.x] [PMID:  18384651] 
[261] 
Fu, L.H.; Qi, C.; Lin, J.; Huang, P. Catalytic chemistry of glucose oxidase in cancer diagnosis and treatment. Chem. Soc. Rev.,  2018, 47(17), 6454-6472.
[http://dx.doi.org/10.1039/C7CS00891K] [PMID:  30024579] 
[262] 
Lin, X.; Wang, Y.; Zhang, Y.; Huang, B.; Lin, J.J.; Hallock, S.J.; Yu, H.; Shao, H.; Yan, J.; Huang, B.; Zhang, X.C.J.; Cao, W.; Xu, X.; Lin, X. Purification and characterization of mutant miniPlasmin for thrombolytic therapy. Thromb. J.,  2013, 11(1), 2.
[http://dx.doi.org/10.1186/1477-9560-11-2] [PMID:  23363549] 
[263] 
Nagai, N.; Demarsin, E.; Van Hoef, B.; Wouters, S.; Cingolani, D.; Laroche, Y.; Collen, D. Recombinant human microplasmin: Production and potential therapeutic properties. J. Thromb. Haemost.,  2003, 1(2), 307-313.
[http://dx.doi.org/10.1046/j.1538-7836.2003.00078.x] [PMID:  12871505] 
[264] 
Thijs, V.N.S.; Peeters, A.; Vosko, M.; Aichner, F.; Schellinger, P.D.; Schneider, D.; Neumann-Haefelin, T.; Röther, J.; Davalos, A.; Wahlgren, N.; Verhamme, P. Randomized, placebo-controlled, dose-ranging clinical trial of intravenous microplasmin in patients with acute ischemic stroke. Stroke,  2009, 40(12), 3789-3795.
[http://dx.doi.org/10.1161/STROKEAHA.109.560201] [PMID:  19834019] 
[265] 
Kaur, N.; Sinha, P.K.; Sahni, G. Site-specific PEGylation of micro-plasmin for improved thrombolytic therapy through engineering enhanced resistance against serpin mediated inhibition. PLoS One,  2019, 14(5)e0217234
[http://dx.doi.org/10.1371/journal.pone.0217234] [PMID:  31141522] 
[266] 
Chen, W.; Huang, X.; Ma, X.W.; Mo, W.; Wang, W.J.; Song, H.Y. Enzymatic vitreolysis with recombinant microplasminogen and tissue plasminogen activator. Eye (Lond.),  2008, 22(2), 300-307.
[http://dx.doi.org/10.1038/sj.eye.6702931] [PMID:  17704761] 
[267] 
de Smet, M.D.; Valmaggia, C.; Zarranz-Ventura, J.; Willekens, B. Microplasmin: Ex vivo characterization of its activity in porcine vitreous. Invest. Ophthalmol. Vis. Sci.,  2009, 50(2), 814-819.
[http://dx.doi.org/10.1167/iovs.08-2185] [PMID:  18806295] 
[268] 
Haller, J.A.; Stalmans, P.; Benz, M.S.; Gandorfer, A.; Pakola, S.J.; Girach, A.; Kampik, A.; Jaffe, G.J.; Toth, C.A.; Grp, M-T.S. Efficacy of intravitreal ocriplasmin for treatment of vitreomacular adhesion: Subgroup analyses from two randomized trials. Ophthalmology,  2015, 122(1), 117-122.
[http://dx.doi.org/10.1016/j.ophtha.2014.07.045] [PMID:  25240630] 
[269] 
de Smet, M.D.; Stassen, J.M.; Meenink, T.C.M.; Janssens, T.; Vanheukelom, V.; Naus, G.J.L.; Beelen, M.J.; Jonckx, B. Release of experimental retinal vein occlusions by direct intraluminal injection of ocriplasmin. Br. J. Ophthalmol.,  2016, 100(12), 1742-1746.
[http://dx.doi.org/10.1136/bjophthalmol-2016-309190] [PMID:  27688592] 
[270] 
Willekens, K.; Gijbels, A.; Smits, J.; Schoevaerdts, L.; Blanckaert, J.; Feyen, J.H.M.; Reynaerts, D.; Stalmans, P. Phase I trial on robot assisted retinal vein cannulation with	ocriplasmin infusion for central retinal vein occlusion. Acta Ophthalmologica,, 
[271] 
Hunt, J.A.; Petteway, S.R., Jr; Scuderi, P.; Novokhatny, V. Simplified recombinant plasmin: Production and functional comparison of a novel thrombolytic molecule with plasma-derived plasmin. Thromb. Haemost.,  2008, 100(3), 413-419.
[http://dx.doi.org/10.1160/TH08-04-0225] [PMID:  18766256] 
[272] 
Sumi, H.; Hamada, H.; Tsushima, H.; Mihara, H.; Muraki, H. A novel fibrinolytic enzyme (nattokinase) in the vegetable cheese Natto; a typical and popular soybean food in the Japanese diet. Experientia,  1987, 43(10), 1110-1111.
[http://dx.doi.org/10.1007/BF01956052] [PMID:  3478223] 
[273] 
Yatagai, C.; Maruyama, M.; Kawahara, T.; Sumi, H. Nattokinase-promoted tissue plasminogen activator release from human cells. Pathophysiol. Haemost. Thromb.,  2008, 36(5), 227-232.
[http://dx.doi.org/10.1159/000252817] [PMID:  19996631] 
[274] 
Urano, T.; Ihara, H.; Umemura, K.; Suzuki, Y.; Oike, M.; Akita, S.; Tsukamoto, Y.; Suzuki, I.; Takada, A. The profibrinolytic enzyme subtilisin NAT purified from Bacillus subtilis Cleaves and inactivates plasminogen activator inhibitor type 1. J. Biol. Chem.,  2001, 276(27), 24690-24696.
[http://dx.doi.org/10.1074/jbc.M101751200] [PMID:  11325965] 
[275] 
Fujita, M.; Ito, Y.; Hong, K.; Nishimuro, S. Characterization of nattokinase-degraded products from human fibrinogen or cross-linked fibrin. Fibrinolysis,  1995, 9(3), 157-164.
[http://dx.doi.org/10.1016/S0268-9499(95)80005-0] 
[276] 
Sumi, H.; Hamada, H.; Nakanishi, K.; Hiratani, H. Enhancement of the fibrinolytic activity in plasma by oral administration of nattokinase. Acta Haematol.,  1990, 84(3), 139-143.
[http://dx.doi.org/10.1159/000205051] [PMID:  2123064] 
[277] 
Fujita, M.; Nomura, K.; Hong, K.; Ito, Y.; Asada, A.; Nishimuro, S. Purification and characterization of a strong fibrinolytic enzyme (nattokinase) in the vegetable cheese natto, a popular soybean fermented food in Japan. Biochem. Biophys. Res. Commun.,  1993, 197(3), 1340-1347.
[http://dx.doi.org/10.1006/bbrc.1993.2624] [PMID:  8280151] 
[278] 
Hsia, C.H.; Shen, M.C.; Lin, J.S.; Wen, Y.K.; Hwang, K.L.; Cham, T.M.; Yang, N.C. Nattokinase decreases plasma levels of fibrinogen, factor VII, and factor VIII in human subjects. Nutr. Res.,  2009, 29(3), 190-196.
[http://dx.doi.org/10.1016/j.nutres.2009.01.009] [PMID:  19358933] 
[279] 
Kurosawa, Y.; Nirengi, S.; Homma, T.; Esaki, K.; Ohta, M.; Clark, J.F.; Hamaoka, T. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles. Sci. Rep.,  2015, 5, 11601.
[http://dx.doi.org/10.1038/srep11601] [PMID:  26109079] 
[280] 
Jensen, G.S.; Lenninger, M.; Ero, M.P.; Benson, K.F. Consumption of nattokinase is associated with reduced blood pressure and von Willebrand factor, a cardiovascular risk marker: Results from a randomized, double-blind, placebo-controlled, multicenter North American clinical trial. Integr. Blood Press. Control,  2016, 9, 95-104.
[http://dx.doi.org/10.2147/IBPC.S99553] [PMID:  27785095] 
[281] 
Pham, P.T.; Han, B.; Hoang, B.X. Nattospes as effective and safe functional supplements in management of stroke. J. Med. Food,  2020, 23(8), 879-885.
[http://dx.doi.org/10.1089/jmf.2019.0183] [PMID:  31934821] 
[282] 
Chen, H.; McGowan, E.M.; Ren, N.; Lal, S.; Nassif, N.; Shad-Kaneez, F.; Qu, X.; Lin, Y. Nattokinase: a promising alternative in prevention and treatment of cardiovascular diseases. Biomark. Insights,  2018, 131177271918785130
[http://dx.doi.org/10.1177/1177271918785130] [PMID:  30013308] 
[283] 
Lichter-Konecki, U.; Vockley, J. Phenylketonuria: Current Treatments and Future Developments. Drugs,  2019, 79(5), 495-500.
[http://dx.doi.org/10.1007/s40265-019-01079-z] [PMID:  30864096] 
[284] 
Al Hafid, N.; Christodoulou, J. Phenylketonuria: A review of current and future treatments. Transl. Pediatr.,  2015, 4(4), 304-317.
[PMID:  26835392] 
[285] 
Vockley, J.; Andersson, H.C.; Antshel, K.M.; Braverman, N.E.; Burton, B.K.; Frazier, D.M.; Mitchell, J.; Smith, W.E.; Thompson, B.H.; Berry, S.A. Phenylalanine hydroxylase deficiency: Diagnosis and management guideline. Genet. Med.,  2014, 16(2), 188-200.
[http://dx.doi.org/10.1038/gim.2013.157] [PMID:  24385074] 
[286] 
Mitchell, J.J.; Trakadis, Y.J.; Scriver, C.R. Phenylalanine hydroxylase deficiency. Genet. Med.,  2011, 13(8), 697-707.
[http://dx.doi.org/10.1097/GIM.0b013e3182141b48] [PMID:  21555948] 
[287] 
Hydery, T.; Coppenrath, V.A. A comprehensive review of pegvaliase, an enzyme substitution therapy for the treatment of phenylketonuria. Drug Target Insights,  2019, 131177392819857089
[http://dx.doi.org/10.1177/1177392819857089] [PMID:  31258325] 
[288] 
Hausmann, O.; Daha, M.; Longo, N.; Knol, E.; Müller, I.; Northrup, H.; Brockow, K. Pegvaliase: Immunological profile and recommendations for the clinical management of hypersensitivity reactions in patients with phenylketonuria treated with this enzyme substitution therapy. Mol. Genet. Metab.,  2019, 128(1-2), 84-91.
[http://dx.doi.org/10.1016/j.ymgme.2019.05.006] [PMID:  31375398] 
[289] 
Ronda, L.; Marchetti, M.; Piano, R.; Liuzzi, A.; Corsini, R.; Percudani, R.; Bettati, S. A Trivalent Enzymatic System for Uricolytic Therapy of HPRT Deficiency and Lesch-Nyhan Disease. Pharm. Res.,  2017, 34(7), 1477-1490.
[http://dx.doi.org/10.1007/s11095-017-2167-6] [PMID:  28508122] 
[290] 
Pfister, D.; Morbidelli, M. Process for protein PEGylation. J. Control. Release,  2014, 180, 134-149.
[http://dx.doi.org/10.1016/j.jconrel.2014.02.002] [PMID:  24531008] 
[291] 
Pasut, G.; Veronese, F.M. State of the art in PEGylation: The great versatility achieved after forty years of research. J. Control. Release,  2012, 161(2), 461-472.
[http://dx.doi.org/10.1016/j.jconrel.2011.10.037] [PMID:  22094104] 
[292] 
Kontos, S.; Hubbell, J.A. Drug development: Longer-lived proteins. Chem. Soc. Rev.,  2012, 41(7), 2686-2695.
[http://dx.doi.org/10.1039/c2cs15289d] [PMID:  22310725] 
[293] 
Hubbell, J.A. Drug development: Longer-lived proteins. Nature,  2010, 467(7319), 1051-1052.
[http://dx.doi.org/10.1038/4671051a] [PMID:  20981086] 
[294] 
Sarkissian, C.N.; Shao, Z.; Blain, F.; Peevers, R.; Su, H.; Heft, R.; Chang, T.M.; Scriver, C.R. A different approach to treatment of phenylketonuria: Phenylalanine degradation with recombinant phenylalanine ammonia lyase. Proc. Natl. Acad. Sci. USA,  1999, 96(5), 2339-2344.
[http://dx.doi.org/10.1073/pnas.96.5.2339] [PMID:  10051643] 
[295] 
Moffitt, M.C.; Louie, G.V.; Bowman, M.E.; Pence, J.; Noel, J.P.; Moore, B.S. Discovery of two cyanobacterial phenylalanine ammonia lyases: Kinetic and structural characterization. Biochemistry,  2007, 46(4), 1004-1012.
[http://dx.doi.org/10.1021/bi061774g] [PMID:  17240984] 
[296] 
Mays, Z.J.; Mohan, K.; Trivedi, V.D.; Chappell, T.C.; Nair, N.U. Directed evolution of Anabaena variabilis phenylalanine ammonia-lyase (PAL) identifies mutants with enhanced activities. Chem. Commun. (Camb.),  2020, 56(39), 5255-5258.
[http://dx.doi.org/10.1039/D0CC00783H] [PMID:  32270162] 
[297] 
Isabella, V.M.; Ha, B.N.; Castillo, M.J.; Lubkowicz, D.J.; Rowe, S.E.; Millet, Y.A.; Anderson, C.L.; Li, N.; Fisher, A.B.; West, K.A.; Reeder, P.J.; Momin, M.M.; Bergeron, C.G.; Guilmain, S.E.; Miller, P.F.; Kurtz, C.B.; Falb, D. Development of a synthetic live bacterial therapeutic for the human metabolic disease phenylketonuria. Nat. Biotechnol.,  2018, 36(9), 857-864.
[http://dx.doi.org/10.1038/nbt.4222] [PMID:  30102294] 
[298] 
McIntosh, I.; Cutting, G.R. Cystic fibrosis transmembrane conductance regulator and the etiology and pathogenesis of cystic fibrosis. FASEB J.,  1992, 6(10), 2775-2782.
[http://dx.doi.org/10.1096/fasebj.6.10.1378801] [PMID:  1378801] 
[299] 
Rowe, S.M.; Miller, S.; Sorscher, E.J. Cystic fibrosis. N. Engl. J. Med.,  2005, 352(19), 1992-2001.
[http://dx.doi.org/10.1056/NEJMra043184] [PMID:  15888700] 
[300] 
O’Sullivan, B.P.; Freedman, S.D. Cystic fibrosis. Lancet,  2009, 373(9678), 1891-1904.
[301] 
Elborn, J.S. Cystic fibrosis. Lancet,  2016, 388(10059), 2519-2531.
[PMID:  27140670] 
[302] 
Ong, T.; Ramsey, B.W. Update in Cystic Fibrosis 2014. Am. J. Respir. Crit. Care Med.,  2015, 192(6), 669-675.
[http://dx.doi.org/10.1164/rccm.201504-0656UP] [PMID:  26371812] 
[303] 
Nazareth, D.; Walshaw, M. Coming of age in cystic fibrosis-transition from paediatric to adult care. Clin. Med. (Lond.),  2013, 13(5), 482-486.
[http://dx.doi.org/10.7861/clinmedicine.13-5-482] [PMID:  24115706] 
[304] 
Sheppard, D.N.; Welsh, M.J. Structure and function of the CFTR chloride channel. Physiol. Rev.,  1999, 79(1)(Suppl.), S23-S45.
[http://dx.doi.org/10.1152/physrev.1999.79.1.S23] [PMID:  9922375] 
[305] 
Bobadilla, J.L.; Macek, M., Jr; Fine, J.P.; Farrell, P.M. Cystic fibrosis: A worldwide analysis of CFTR mutations--correlation with incidence data and application to screening. Hum. Mutat.,  2002, 19(6), 575-606.
[http://dx.doi.org/10.1002/humu.10041] [PMID:  12007216] 
[306] 
Sharma, J.; Keeling, K.M.; Rowe, S.M. Pharmacological approaches for targeting cystic fibrosis nonsense mutations. Eur. J. Med. Chem.,  2020, 200112436
[http://dx.doi.org/10.1016/j.ejmech.2020.112436] [PMID:  32512483] 
[307] 
Guimbellot, J.; Sharma, J.; Rowe, S.M. Toward inclusive therapy with CFTR modulators: Progress and challenges. Pediatr. Pulmonol.,  2017, 52(S48), S4-S14.
[http://dx.doi.org/10.1002/ppul.23773] [PMID:  28881097] 
[308] 
Elborn, J.S.; Davies, J. Clinical trial research in focus: Ensuring new cystic fibrosis drugs fulfil their potential. Lancet Respir. Med.,  2017, 5(9), 681-683.
[http://dx.doi.org/10.1016/S2213-2600(17)30311-9] [PMID:  28853396] 
[309] 
Birket, S.E.; Chu, K.K.; Houser, G.H.; Liu, L.; Fernandez, C.M.; Solomon, G.M.; Lin, V.; Shastry, S.; Mazur, M.; Sloane, P.A.; Hanes, J.; Grizzle, W.E.; Sorscher, E.J.; Tearney, G.J.; Rowe, S.M. Combination therapy with cystic fibrosis transmembrane conductance regulator modulators augment the airway functional microanatomy. Am. J. Physiol. Lung Cell. Mol. Physiol.,  2016, 310(10), L928-L939.
[http://dx.doi.org/10.1152/ajplung.00395.2015] [PMID:  26968770] 
[310] 
Yang, C.; Montgomery, M. Dornase alfa for cystic fibrosis. Cochrane Database Syst. Rev.,  2018, 9CD001127
[PMID:  30187450] 
[311] 
Yang, C.L.; Chilvers, M.; Montgomery, M.; Nolan, S.J. Dornase alfa for cystic fibrosis. Paediatr. Respir. Rev.,  2017, 21, 65-67.
[PMID:  27769785] 
[312] 
Lieberman, J. Dornase aerosol effect on sputum viscosity in cases of cystic fibrosis. JAMA,  1968, 205(5), 312-313.
[http://dx.doi.org/10.1001/jama.1968.03140310070022] [PMID:  5694947] 
[313] 
Cramer, G.W.; Bosso, J.A. The role of dornase alfa in the treatment of cystic fibrosis. Ann. Pharmacother.,  1996, 30(6), 656-661.
[http://dx.doi.org/10.1177/106002809603000614] [PMID:  8792953] 
[314] 
Parsiegla, G.; Noguere, C.; Santell, L.; Lazarus, R.A.; Bourne, Y. The structure of human DNase I bound to magnesium and phosphate ions points to a catalytic mechanism common to members of the DNase I-like superfamily. Biochemistry,  2012, 51(51), 10250-10258.
[http://dx.doi.org/10.1021/bi300873f] [PMID:  23215638] 
[315] 
Collier, J. Dornase-alfa and orphan drugs. Lancet,  1995, 346(8975), 633-633.
[http://dx.doi.org/10.1016/S0140-6736(95)91460-9] [PMID:  7651014] 
[316] 
Shak, S.; Capon, D.J.; Hellmiss, R.; Marsters, S.A.; Baker, C.L. Recombinant human DNase I reduces the viscosity of cystic fibrosis sputum. Proc. Natl. Acad. Sci. USA,  1990, 87(23), 9188-9192.
[http://dx.doi.org/10.1073/pnas.87.23.9188] [PMID:  2251263] 
[317] 
Erdeve, O.; Uras, N.; Atasay, B.; Arsan, S. Efficacy and safety of nebulized recombinant human DNase as rescue treatment for persistent atelectasis in newborns: Case-series. Croat. Med. J.,  2007, 48(2), 234-239.
[PMID:  17436388] 
[318] 
Hendriks, T.; de Hoog, M.; Lequin, M.H.; Devos, A.S.; Merkus, P.J.F.M. DNase and atelectasis in non-cystic fibrosis pediatric patients. Crit. Care,  2005, 9(4), R351-R356.
[http://dx.doi.org/10.1186/cc3544] [PMID:  16137347] 
[319] 
Brinkmann, V.; Reichard, U.; Goosmann, C.; Fauler, B.; Uhlemann, Y.; Weiss, D.S.; Weinrauch, Y.; Zychlinsky, A. Neutrophil extracellular traps kill bacteria. Science,  2004, 303(5663), 1532-1535.
[http://dx.doi.org/10.1126/science.1092385] [PMID:  15001782] 
[320] 
Papayannopoulos, V.; Staab, D.; Zychlinsky, A. Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy. PLoS One,  2011, 6(12)e28526
[http://dx.doi.org/10.1371/journal.pone.0028526] [PMID:  22174830] 
[321] 
Barnes, B.J.; Adrover, J.M.; Baxter-Stoltzfus, A.; Borczuk, A.; Cools-Lartigue, J.; Crawford, J.M.; Daßler-Plenker, J.; Guerci, P.; Huynh, C.; Knight, J.S.; Loda, M.; Looney, M.R.; McAllister, F.; Rayes, R.; Renaud, S.; Rousseau, S.; Salvatore, S.; Schwartz, R.E.; Spicer, J.D.; Yost, C.C.; Weber, A.; Zuo, Y.; Egeblad, M. Targeting potential drivers of COVID-19: Neutrophil extracellular traps. J. Exp. Med.,  2020, 217(6)e20200652
[http://dx.doi.org/10.1084/jem.20200652] [PMID:  32302401] 
[322] 
Skovbjerg, H.; Sjöström, H.; Norén, O. Purification and characterisation of amphiphilic lactase/phlorizin hydrolase from human small intestine. Eur. J. Biochem.,  1981, 114(3), 653-661.
[http://dx.doi.org/10.1111/j.1432-1033.1981.tb05193.x] [PMID:  6786877] 
[323] 
Swallow, D.M. Genetics of lactase persistence and lactose intolerance. Annu. Rev. Genet.,  2003, 37, 197-219.
[http://dx.doi.org/10.1146/annurev.genet.37.110801.143820] [PMID:  14616060] 
[324] 
Mantei, N.; Villa, M.; Enzler, T.; Wacker, H.; Boll, W.; James, P.; Hunziker, W.; Semenza, G. Complete primary structure of human and rabbit lactase-phlorizin hydrolase: Implications for biosynthesis, membrane anchoring and evolution of the enzyme. EMBO J.,  1988, 7(9), 2705-2713.
[http://dx.doi.org/10.1002/j.1460-2075.1988.tb03124.x] [PMID:  2460343] 
[325] 
Fassio, F.; Facioni, M.S.; Guagnini, F. Lactose Maldigestion, Malabsorption, and Intolerance: A Comprehensive Review with a Focus on Current Management and Future Perspectives. Nutrients,  2018, 10(11)E1599
[http://dx.doi.org/10.3390/nu10111599] [PMID:  30388735] 
[326] 
Leis, R.; de Castro, M.J.; de Lamas, C.; Picáns, R.; Couce, M.L. Effects of prebiotic and probiotic supplementation on lactase deficiency and lactose intolerance: a systematic review of controlled trials. Nutrients,  2020, 12(5)E1487
[http://dx.doi.org/10.3390/nu12051487] [PMID:  32443748] 
[327] 
Szilagyi, A.; Ishayek, N. Lactose intolerance, dairy avoidance, and treatment options. Nutrients,  2018, 10(12)E1994
[http://dx.doi.org/10.3390/nu10121994] [PMID:  30558337] 
[328] 
Portincasa, P.; Di Ciaula, A.; Vacca, M.; Montelli, R.; Wang, D.Q.; Palasciano, G. Beneficial effects of oral tilactase on patients with hypolactasia. Eur. J. Clin. Invest.,  2008, 38(11), 835-844.
[http://dx.doi.org/10.1111/j.1365-2362.2008.02035.x] [PMID:  19021701] 
[329] 
Ojetti, V.; Gigante, G.; Gabrielli, M.; Ainora, M.E.; Mannocci, A.; Lauritano, E.C.; Gasbarrini, G.; Gasbarrini, A. The effect of oral supplementation with Lactobacillus reuteri or tilactase in lactose intolerant patients: Randomized trial. Eur. Rev. Med. Pharmacol. Sci.,  2010, 14(3), 163-170.
[PMID:  20391953] 
[330] 
de Vrese, M.; Laue, C.; Offick, B.; Soeth, E.; Repenning, F.; Thoß, A.; Schrezenmeir, J. A combination of acid lactase from Aspergillus oryzae and yogurt bacteria improves lactose digestion in lactose maldigesters synergistically: A randomized, controlled, double-blind cross-over trial. Clin. Nutr.,  2015, 34(3), 394-399.
[http://dx.doi.org/10.1016/j.clnu.2014.06.012] [PMID:  25042846] 
[331] 
Ibba, I.; Gilli, A.; Boi, M.F.; Usai, P. Effects of exogenous lactase administration on hydrogen breath excretion and intestinal symptoms in patients presenting lactose malabsorption and intolerance. BioMed Res. Int.,  2014, 2014680196
[http://dx.doi.org/10.1155/2014/680196] [PMID:  24967391] 
[332] 
Scientific Opinion on the substantiation of health claims related to zinc and function of the immune system (ID 291, 1757), DNA synthesis and cell division (ID 292, 1759), protection of DNA, proteins and lipids from oxidative damage (ID 294, 1758), maintenance of bone (ID 295, 1756), cognitive function (ID 296), fertility and reproduction (ID 297, 300), reproductive development (ID 298), muscle function (ID 299), metabolism of fatty acids (ID 302), maintenance of joints (ID 305), function of the heart and blood vessels (ID 306), prostate function (ID 307), thyroid function (ID 308), acid-base metabolism (ID 360), vitamin A metabolism (ID 361) and maintenance of vision (ID 361) pursuant to Article 13(1) of Regulation (EC) No 1924/2006. EFSA. EFSA J.,  2009, 7(9)
[333] 
Jenner, J.R.; Buttle, D.J.; Dixon, A.K. Mechanism of action of intradiscal chymopapain in the treatment of sciatica: A clinical, biochemical, and radiological study. Ann. Rheum. Dis.,  1986, 45(6), 441-449.
[http://dx.doi.org/10.1136/ard.45.6.441] [PMID:  3729572] 
[334] 
Matsuyama, Y.; Chiba, K. Condoliase for treatment of lumbar disc herniation. Drugs Today (Barc),  2019, 55(1), 17-23.
[http://dx.doi.org/10.1358/dot.2019.55.1.2899445] [PMID:  30740609] 
[335] 
Ebata, M.; Yasunobu, K.T.; Chymopapain, I.; Chymopapain, I. Isolation, crystallization, and preliminary characterization. J. Biol. Chem.,  1962, 237, 1086-1094.
[http://dx.doi.org/10.1016/S0021-9258(18)60289-3] [PMID:  13888995] 
[336] 
Maes, D.; Bouckaert, J.; Poortmans, F.; Wyns, L.; Looze, Y. Structure of chymopapain at 1.7 A resolution. Biochemistry,  1996, 35(50), 16292-16298.
[http://dx.doi.org/10.1021/bi961491w] [PMID:  8973203] 
[337] 
Henschke, N.; Kuijpers, T.; Rubinstein, S.M.; van Middelkoop, M.; Ostelo, R.; Verhagen, A.; Koes, B.W.; van Tulder, M.W. Injection therapy and denervation procedures for chronic low-back pain: A systematic review. Eur. Spine J.,  2010, 19(9), 1425-1449.
[http://dx.doi.org/10.1007/s00586-010-1411-0] [PMID:  20424870] 
[338] 
Simmons, J.W.; Upman, P.J.; Stavinoha, W.B. Pharmacologic and toxicologic profile of chymopapain B (Chemolase). Drug Chem. Toxicol.,  1984, 7(3), 299-314.
[http://dx.doi.org/10.3109/01480548409035110] [PMID:  6376060] 
[339] 
Cusick, J.F.; Ho, K.C.; Schamberg, J.F. Subarachnoid hemorrhage following chymopapain chemonucleolysis. Case report. J. Neurosurg.,  1987, 66(5), 775-778.
[http://dx.doi.org/10.3171/jns.1987.66.5.0775] [PMID:  3572504] 
[340] 
Dyck, P. Paraplegia following chemonucleolysis. A case report and discussion of neurotoxicity. Spine,  1985, 10(4), 359-362.
[http://dx.doi.org/10.1097/00007632-198505000-00012] [PMID:  2931832] 
[341] 
Buchman, A.; Wright, R.B.; Wichter, M.D.; Whisler, W.W.; Bosch, A. Hemorrhagic complications after the lumbar injection of chymopapain. Neurosurgery,  1985, 16(2), 222-224.
[http://dx.doi.org/10.1227/00006123-198502000-00017] [PMID:  3883224] 
[342] 
Ishibashi, K.; Iwai, H.; Koga, H. Chemonucleolysis with chondroitin sulfate ABC endolyase as a novel minimally invasive treatment for patients with lumbar intervertebral disc herniation. J. Spine Surg.,  2019, 5(Suppl. 1), S115-S121.
[http://dx.doi.org/10.21037/jss.2019.04.24] [PMID:  31380500] 
[343] 
Hedtmann, A.; Steffen, R.; Krämer, J. Prospective comparative study of intradiscal high-dose and low-dose collagenase Versus chymopapain. Spine,  1987, 12(4), 388-392.
[http://dx.doi.org/10.1097/00007632-198705000-00016] [PMID:  3039670] 
[344] 
Zook, B.C.; Kobrine, A.I. Effects of collagenase and chymopapain on spinal nerves and intervertebral discs of cynomolgus monkeys. J. Neurosurg.,  1986, 64(3), 474-483.
[http://dx.doi.org/10.3171/jns.1986.64.3.0474] [PMID:  3005529] 
[345] 
Sussman, B.J.; Bromley, J.W.; Gomez, J.C. Injection of collagenase in the treatment of herniated lumbar disk. Initial clinical report. JAMA,  1981, 245(7), 730-732.
[http://dx.doi.org/10.1001/jama.1981.03310320052026] [PMID:  6257939] 
[346] 
Huang, W.; Lunin, V.V.; Li, Y.; Suzuki, S.; Sugiura, N.; Miyazono, H.; Cygler, M. Crystal structure of Proteus vulgaris chondroitin sulfate ABC lyase I at 1.9A resolution. J. Mol. Biol.,  2003, 328(3), 623-634.
[http://dx.doi.org/10.1016/S0022-2836(03)00345-0] [PMID:  12706721] 
[347] 
Benito-Arenas, R.; Zarate, S.G.; Revuelta, J.; Bastida, A. Chondroitin sulfate-degrading enzymes as tools for the development of new pharmaceuticals. Catalysts,  2019, 9(4)
[http://dx.doi.org/10.3390/catal9040322] 
[348] 
Hettiaratchi, M.H.; O’Meara, M.J.; O’Meara, T.R.; Pickering, A.J.; Letko-Khait, N.; Shoichet, M.S. Reengineering biocatalysts: Computational redesign of chondroitinase ABC improves efficacy and stability. Sci. Adv.,  2020, 6(34)eabc6378
[http://dx.doi.org/10.1126/sciadv.abc6378] [PMID:  32875119] 
[349] 
Chiba, K.; Matsuyama, Y.; Seo, T.; Toyama, Y. Condoliase for the treatment of lumbar disc herniation: a randomized controlled trial. Spine,  2018, 43(15), E869-E876.
[http://dx.doi.org/10.1097/BRS.0000000000002528] [PMID:  29257028] 
[350] 
Matsuyama, Y.; Chiba, K.; Iwata, H.; Seo, T.; Toyama, Y. A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation. J. Neurosurg. Spine,  2018, 28(5), 499-511.
[http://dx.doi.org/10.3171/2017.7.SPINE161327] [PMID:  29424676] 
[351] 
Pilcher, B.K.; Wang, M.; Qin, X.J.; Parks, W.C.; Senior, R.M.; Welgus, H.G. Role of matrix metalloproteinases and their inhibition in cutaneous wound healing and allergic contact hypersensitivity. Ann. N. Y. Acad. Sci.,  1999, 878, 12-24.
[http://dx.doi.org/10.1111/j.1749-6632.1999.tb07671.x] [PMID:  10415717] 
[352] 
Vogel, W.F. Collagen-receptor signaling in health and disease. Eur. J. Dermatol.,  2001, 11(6), 506-514.
[PMID:  11701397] 
[353] 
Balbín, M.; Fueyo, A.; Knäuper, V.; Pendás, A.M.; López, J.M.; Jiménez, M.G.; Murphy, G.; López-Otín, C. Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. J. Biol. Chem.,  1998, 273(37), 23959-23968.
[http://dx.doi.org/10.1074/jbc.273.37.23959] [PMID:  9727011] 
[354] 
Duarte, A.S.; Correia, A.; Esteves, A.C. Bacterial collagenases-A review. Crit. Rev. Microbiol.,  2016, 42(1), 106-126.
[http://dx.doi.org/10.3109/1040841X.2014.904270] [PMID:  24754251] 
[355] 
Gross, J.; Nagai, Y. Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc. Natl. Acad. Sci. USA,  1965, 54(4), 1197-1204.
[http://dx.doi.org/10.1073/pnas.54.4.1197] [PMID:  4286832] 
[356] 
Eckhard, U.; Huesgen, P.F.; Brandstetter, H.; Overall, C.M. Proteomic protease specificity profiling of clostridial collagenases reveals their intrinsic nature as dedicated degraders of collagen. J. Proteomics,  2014, 100(100), 102-114.
[http://dx.doi.org/10.1016/j.jprot.2013.10.004] [PMID:  24125730] 
[357] 
Bond, M.D.; Van Wart, H.E. Purification and separation of individual collagenases of Clostridium histolyticum using red dye ligand chromatography. Biochemistry,  1984, 23(13), 3077-3085.
[http://dx.doi.org/10.1021/bi00308a035] [PMID:  6087887] 
[358] 
Bond, M.D.; Van Wart, H.E. Characterization of the individual collagenases from Clostridium histolyticum. Biochemistry,  1984, 23(13), 3085-3091.
[http://dx.doi.org/10.1021/bi00308a036] [PMID:  6087888] 
[359] 
Bond, M.D.; Van Wart, H.E. Relationship between the individual collagenases of Clostridium histolyticum: Evidence for evolution by gene duplication. Biochemistry,  1984, 23(13), 3092-3099.
[http://dx.doi.org/10.1021/bi00308a037] [PMID:  6087889] 
[360] 
Worthington, K.; Worthington, V. Worthington Enzyme Manual, 2011.Available from:. http://www.worthington-biochem.com/pap/default.html Worthington Biochemical	Corporation.
[361] 
French, M.F.; Bhown, A.; Van Wart, H.E. Identification of Clostridium histolyticum collagenase hyperreactive sites in type I, II, and III collagens: Lack of correlation with local triple helical stability. J. Protein Chem.,  1992, 11(1), 83-97.
[http://dx.doi.org/10.1007/BF01025095] [PMID:  1325154] 
[362] 
Matsushita, O.; Jung, C.M.; Katayama, S.; Minami, J.; Takahashi, Y.; Okabe, A. Gene duplication and multiplicity of collagenases in Clostridium histolyticum. J. Bacteriol.,  1999, 181(3), 923-933.
[http://dx.doi.org/10.1128/JB.181.3.923-933.1999] [PMID:  9922257] 
[363] 
Eckhard, U.; Schönauer, E.; Nüss, D.; Brandstetter, H. Structure of collagenase G reveals a chew-and-digest mechanism of bacterial collagenolysis. Nat. Struct. Mol. Biol.,  2011, 18(10), 1109-1114.
[http://dx.doi.org/10.1038/nsmb.2127] [PMID:  21947205] 
[364] 
Wilson, J.J.; Matsushita, O.; Okabe, A.; Sakon, J. A bacterial collagen-binding domain with novel calcium-binding motif controls domain orientation. EMBO J.,  2003, 22(8), 1743-1752.
[http://dx.doi.org/10.1093/emboj/cdg172] [PMID:  12682007] 
[365] 
Eckhard, U.; Schönauer, E.; Brandstetter, H. Structural basis for activity regulation and substrate preference of clostridial collagenases G, H, and T. J. Biol. Chem.,  2013, 288(28), 20184-20194.
[http://dx.doi.org/10.1074/jbc.M112.448548] [PMID:  23703618] 
[366] 
Dhillon, S. Collagenase clostridium histolyticum: a review in Peyronie’s disease. Drugs,  2015, 75(12), 1405-1412.
[http://dx.doi.org/10.1007/s40265-015-0441-7] [PMID:  26201462] 
[367] 
Kaplan, F.T. Collagenase clostridium histolyticum injection for the treatment of Dupuytren’s contracture. Drugs Today (Barc),  2011, 47(9), 653-667.
[http://dx.doi.org/10.1358/dot.2011.47.9.1656502] [PMID:  21971540] 
[368] 
Ramundo, J.; Gray, M. Collagenase for enzymatic debridement: A systematic review. J. Wound Ostomy Continence Nurs.,  2009, 36(6)(Suppl.), S4-S11.
[http://dx.doi.org/10.1097/WON.0b013e3181bfdf83] [PMID:  19918148] 
[369] 
Available from. https://www.accessdata.fda.gov/drugsatfda_ docs/l abel/2020/761146s000lbl.pdf
[370] 
Randhawa, K.; Shukla, C.J. Non-invasive treatment in the management of Peyronie’s disease. Ther. Adv. Urol.,  2019, 11(11)1756287218823671
[http://dx.doi.org/10.1177/1756287218823671] [PMID:  30792820] 
[371] 
Available from. https://www.accessdata.fda.gov/drugsatfda_ docs/label/2018/125338s109lbl.pdf
[372] 
Available from. https://www.ema.europa.eu/en/documents/product-information/xiapex-epar-product-information_it.pdf
[373] 
Grazina, R.; Teixeira, S.; Ramos, R.; Sousa, H.; Ferreira, A.; Lemos, R. Dupuytren’s disease: Where do we stand? EFORT Open Rev.,  2019, 4(2), 63-69.
[http://dx.doi.org/10.1302/2058-5241.4.180021] [PMID:  30931150] 
[374] 
Nayar, S.K.; Pfisterer, D.; Ingari, J.V. Collagenase Clostridium Histolyticum Injection for Dupuytren Contracture: 2-Year Follow-up. Clin. Orthop. Surg.,  2019, 11(3), 332-336.
[http://dx.doi.org/10.4055/cios.2019.11.3.332] [PMID:  31475055] 
[375] 
Hurst, L.C.; Badalamente, M.A.; Hentz, V.R.; Hotchkiss, R.N.; Kaplan, F.T.; Meals, R.A.; Smith, T.M.; Rodzvilla, J. Injectable collagenase clostridium histolyticum for Dupuytren’s contracture. N. Engl. J. Med.,  2009, 361(10), 968-979.
[http://dx.doi.org/10.1056/NEJMoa0810866] [PMID:  19726771] 
[376] 
Gelbard, M.; Goldstein, I.; Hellstrom, W.J.; McMahon, C.G.; Smith, T.; Tursi, J.; Jones, N.; Kaufman, G.J.; Carson, C.C. III Clinical efficacy, safety and tolerability of collagenase clostridium histolyticum for the treatment of peyronie disease in 2 large double-blind, randomized, placebo controlled phase 3 studies. J. Urol.,  2013, 190(1), 199-207.
[http://dx.doi.org/10.1016/j.juro.2013.01.087] [PMID:  23376148] 
[377] 
Pham, C.H.; Collier, Z.J.; Fang, M.; Howell, A.; Gillenwater, T.J. T.J. The role of collagenase ointment in acute burns:
	A systematic review and meta-analysis. J Wound Care,
	2019, 28(Sup2), S9-S15., 
[http://dx.doi.org/10.12968/jowc.2019.28.Sup2.S9] 
[378] 
Available from. https://www.ema.europa.eu/en/documents/product-information/nexobrid-epar-product-information_en. pdf
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DOI https://dx.doi.org/10.2174/0929867328666210713094722	Print ISSN 0929-8673
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