Abstract
Diabetes mellitus is an emerging predator and affecting around 422 million adults worldwide. Higher levels of circulating insulin and increased pressure on the pancreas to produce insulin have been inferred as possible etiology for diabetes leading to a higher risk of pancreatic cancer. Out of several drug targets in hypoglycemic discovery, Dipeptidyl peptidase-IV (DPP-IV) has been considered an emerging target. It is a protease enzyme which inactivates incretin hormones i.e., Glucagonlike peptide 1 (GLP-1) and glucose-dependent insulin tropic polypeptide (GIP). Inhibition of DPP-4 results in the longer action of GLP-1 and GIP, therefore, DPP-4 inhibitors play an important role in maintaining glucose homeostasis. In comparison to early oral hypoglycemic, DPP-IV inhibitors are well tolerated and provide a better glycemic control over a longer period. These enzymes are expressed in a dimeric form on the surface of different cells such as prostate, liver and small intestinal epithelium cells. Disruption of the local signaling environment is an emerging factor in cancer development. Till date, not even a single DPP-IV inhibitor as anticancer has been developed. This review focuses on various features of the enzyme and their suitable inhibitors for target disease.
Keywords: Dipeptidyl peptidase-IV, diabetes, cancer, peptide-1, glucose homeostasis, diabetes mellitus.
Graphical Abstract
[1]
Giovannucci, E.; David, M.H.; Michael, C.A.; Richard, M.B.; Susan, M.G.; Laurel, A.H. Michael. P.; Regensteiner, J.G.; Douglas, Y. Diabetes and Cancer. A consensus report. Diabetes Care, 2010, 33(7), 1674-1685.
[2]
Guojing, L.; Hong, L.; and Hongyun, L. Glucagon‐like peptide‐1(GLP‐1) receptor agonists: potential to reduce fracture risk in diabetic patients? J. Clin. Pharmacol., 2016, 81(1), 78-88.
[3]
Chinmay, S.M.; Christopher, K.R.; Karen, L.J.; Michael, H. Diabetes Care, 2013, 36(5), 1396-1405.
[4]
Kieffer, T.J.; Mclntosh, C.H.; Pederson, R.A. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagonlike peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology, 1995, 136, 3585-3596.
[5]
Meier, J.J.; Nauck, M.A.; Schmidt, W.E.; Gallwitz, B. Gastric inhibitory polypeptide: The neglected incretin revisited. Regul. Pept., 2002, 107(1-3), 1-13.
[6]
Egan, J.M.; Bulotta, A.; Hui, H.; Perfetti, R. GLP-1 receptor agonists are growth and differentiation factors for pancreatic islet beta cells. Diabetes Metab. Res. Rev., 2003, 19(2), 115-123.
[7]
Murphy, K.G.; Dhillo, W.S.; Bloom, S.R. Gut peptides in the regulation of food intake and energy homeostasis. Endocr. Rev., 2006, 27(7), 719-727.
[8]
Mclntosh, C.H.S. Dipeptidyl peptidase IV inhibitors and diabetes therapy. Front. Biosci Landmark Ed., 2008, 13, 1753-1773.
[9]
Matteucci, E.; Giampietro, O. Dipeptidyl peptidase-4 (CD26): knowing the functionbefore inhibiting the enzyme. Curr. Med. Chem., 2009, 16(23), 2943-2951.
[10]
aKshirsagar, A.D.; Aggarwal, A.S.; Harle, U.N.; Deshpande, A.D. DPP IV inhibitors: Successes, failures and future prospects. Diabetes Metab. Syndr., 2011, 5, 105-112.
bAbbott, C.A.; Baker, E.; Sutherland, G.R.; McCaughan, G.W. Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics, 1994, 40, 31-38.
bAbbott, C.A.; Baker, E.; Sutherland, G.R.; McCaughan, G.W. Genomic organization, exact localization, and tissue expression of the human CD26 (dipeptidyl peptidase IV) gene. Immunogenetics, 1994, 40, 31-38.
[11]
Cheng, H.C.; Abdel-Ghany, M.; Elble, R.C.; Pauli, B.U. Lung endothelial dipeptidyl peptidase IV promotes adhesion and metastasis of rat breast cancer cells via tumor cell surface-associated fibronectin. J. Biol. Chem., 1998, 273(37), 24207-24215.
[12]
Pethiyagoda, C.L.; Welch, D.R.; Fleming, T.P. Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. Clin. Exp. Metastasis, 2000, 18(5), 391-400.
[13]
Aytac, U.; Claret, F.X.; Ho, L.; Sato, K.; Ohnuma, K.; Mills, G.B.; Cabanillas, F.; Morimoto, C.; Dang, N.H. Expression of CD26 and its associated dipeptidyl peptidase IV enzyme activity enhances sensitivity to doxorubicin-induced cell cycle arrest at the G(2)/M checkpoint. Cancer Res., 2001, 61(19), 7204-7210.
[14]
Wesley, U.V.; Albino, A.P.; Tiwari, S.; Houghton, A.N. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. J. Exp. Med., 1999, 190(3), 311-322.
[15]
Engel, M.; Hoffmann, T.; Manhart, S.; Heiser, U.; Chambre, S.; Huber, R.; Demuth, H.U.; Bode, W. Rigidity and flexibility of dipeptidyl peptidase IV: crystal structures of and docking experiments with DPIV. J. Mol. Biol., 2006, 355(4), 768-783.
[16]
Kuhn, B.; Hennig, M.; Mattei, P. Molecular recognition of ligands in dipeptidyl peptidase IV. Curr. Top. Med. Chem., 2007, 7(6), 609-619.
[17]
Watanabe, Y.S.; Yasuda, Y.; Kojima, Y.; Okada, S.; Motoyama, T.; Takahashi, R.; Oka, M. Anagliptin, a potent dipeptidyl peptidase IV inhibitor: Its single-crystal structure and enzyme interactions. J. Enzyme Inhib. Med. Chem., 2015, 30(6), 981-988.
[18]
Lucienne, J.J. Dipeptidyl Peptidase IV and Its Inhibitors: Therapeutics for Type 2 Diabetes and What Else? J. Med. Chem., 2014, 57(6), 2197-2212.
[19]
Rotella, D.P. Novel Second-Generation approaches for the control of type 2 diabetes. J. Med. Chem., 2004, 47(17), 4111-4112.
[20]
Weber, A.E. Dipeptidyl Peptidase IV Inhibitors for the treatment of Diabetes. J. Med. Chem., 2004, 47(17), 4135-4141.
[21]
Gorrell, M.D. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin. Sci. (Lond.), 2005, 108(4), 277-292.
[22]
Struyf, S.; Proost, P.; Schols, D. E.D.; Clercq, E.D.; Opdenakker, G.; Jean-Pierre, L.; Detheux, M.; Parmentier, M.; Meester, I.D.; Simmon, S.; Damme, J.V. CD26/Dipeptidyl-peptidase IV down-regulates the eosinophil chemotactic potency, but not the anti-HIV activity of human eotaxin by affecting its interaction with CC chemokine receptor 3. J. Immunol., 1999, 162(8), 4903-4909.
[23]
Sedo, A.; Duke-Cohan, J. S.; Balaziova, E.; Sedova, L, R. Dipeptidyl peptidase IV activity and/or structure homologs: Contributing factors in the pathogenesis of rheumatoid arthritis? Arthritis Res. Ther., 2005, 7, 253-269.
[24]
Detel, D.; Kehler, T.; Buljevic, S.; Pavacic, I.; Pucar, L.B.; Varljen, N.; Varljen, J. Is dipeptidyl peptidase IV (DPP IV) associated with inflammation present in human spondyloarthritides and rheumatoid arthritis. Croat. Chem. Acta, 2012, 85(2), 231-238.
[25]
Gotoh, H.; Haglhara, M.; Nagateu, T.; Iwata, H.; Mlura, T. Activities of dipeptidyl peptidase II and dipeptidyl peptidase IV in synovial fluid from patients with rheumatoid arthritis and osteoarthritis. Clin. Chem., 1989, 35(6), 1016-1018.
[26]
Rossi, D.; Zlotnik, A. The biology of chemokines and their receptors. Annu. Rev. Immunol., 2000, 18, 217-242.
[27]
Kim, D.; Wang, L.; Beconi, M.; Eiermann, G.J.; Fisher, M.H.; He, H.; Hickey, G.J.; Kowalchick, J.E.; Leiting, B.; Lyons, K.; Marsilio, F.; McCann, M.E.; Patel, R.A.; Petrov, A.; Scapin, G.; Patel, S.B.; Sinha, R.; Wu, J.K.; Wyvratt, M.J.; Zhang, B.B.; Zhu, L.; Thornberry, N.A.; Weber, A.E. (2R)-4-Oxo-4-[3-(trifuloromethyl)- 5,6-dihydro [1,2,4]triazolo [4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluo-rophenyl) butan-2-amine: A potent orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2005, 48(1), 141-151.
[28]
Villhauer, E.B.; Brinkman, J.A.; Naderi, G.B.; Burkey, B.N.F.; Dunning, B.E.; Prasad, K.; Mangold, B.L.; Russell, M.E.; Hughes, T.E. 1-3[(3-Hydroxy-1-adamantyl)amino] acetyl-2-cyano-(S)-pyrrolidine, a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem., 2003, 46(13), 2774-2789.
[29]
Augeri, D.J.; Robl, J.A.; Khanna, A.; Robertson, J.G.; Wang, A.; Simpkins, L.M.; Taunk, P.; Huang, Q.; Han, S.P.; Abboa-Offei, B.; Cap, M.; Xin, L.; Tao, L.; Tozzo, E.; Welzel, G.E.; Egan, D.M.; Marcinkeviciene, J.; Chang, S.Y.; Biller, S.A.; Kirby, M.S.; Parker, R.A.; Hamann, L.G. Discovery and preclinical profile of saxagliptin (BMS-477118): A highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2005, 48(15), 5025-5037.
[30]
Feng, J.; Zhang, Z.; Wallace, M.; Stafford, J.; Kaldor, S.; Kassel, D.; Navre, M.; Shi, L. Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem., 2007, 50(10), 2297-2300.
[31]
Eckhardt, M.; Langkop, E.; Mark, M.; Tadayyon, M.; Thomas, L.; Nar, H.; Pfengle, W.; Guth, B.; Lotz, R.; Siegel, P.; Fuchs, H.; Himmelsbach, E. 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3- methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine- 2,6-dione (BI-1356) a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type-2 diabetes. J. Med. Chem., 2007, 50(26), 6450-6453.
[32]
Lim, K.S.; Cho, J.Y.; Kim, B.H.; Kim, J.R.; Kim, H.S.; Kim, D.K.; Kim, S.H.; Yim, H.J.; Lee, S.H.; Shin, S.G.; Jang, I.J.; Yu, K.S. Pharmacokinetics and pharmacodynamics of LC15-0444, a novel dipeptidyl peptidase IV inhibitors, after multiple dosing in healthy volunteers. Br. J. Clin. Pharmacol., 2009, 68(6), 883-890.
[33]
Yang, S.J.; Min, K.W.; Gupta, S.K.; Park, J.Y.; Shivane, V.K.; Pitale, S.U.; Agarwal, P.K.; Sosale, A.; Gandhi, P.; Dharmalingam, M.; Mohan, V.; Makesh, U.; Kim, D.M.; Kim, J.A.; Kim, P.K.; Baik, S.H. A multicentre, multinational, randomized, placebo-controlled, doubleblind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15-0444) in patients with type 2 diabetes. Diabetes Obes. Metab., 2013, 15(5), 410-416.
[34]
Kim, M.K.; Chae, Y.N.; Kim, H.D.; Yang, E.K.; Cho, E.J.; Choi, S.H.; Cheong, Y.H.; Kim, H.S.; Kim, H.J.; Jo, Y.W.; Son, M.H.; Kim, S.H.; Shin, C.Y. DA-1229, a novel and potent DPP4 inhibitor, improves insulin resistance and delays the onset of diabetes. Life Sci., 2012, 90, 21-29.
[35]
Yasuda, N.; Nagakura, T.; Inoue, T.; Yamazaki, K.; Katsutani, N.; Takenaka, O.; Clark, R.; Matsuura, F.; Emori, E.; Yoshikawa, S.; Kira, K.; Ikuta, H.; Okada, T.; Saeki, T.; Asano, O.; Tanaka, I. E3024, 3-but-2-ynyl-5-methyl-2-piperazin-1-yl-3,5-dihydro-4H-imidazo [4,5-d]- pyridazin-4-one tosylate, is a novel, selective and competitive dipeptidyl peptidase IV inhibitor. Eur. J. Pharmacol., 2000, 548(1-3), 181-187.
[36]
Miyamoto, Y.; Banno, Y.; Yamashita, T.; Fujimoto, T.; Oi, S.; Moritoh, Y.; Asakawa, T.; Kataoka, O.; Takeuchi, K.; Suzuki, N.; Ikedo, K.; Kosaka, T.; Tsubotani, S.; Tani, A.; Sasaki, M.; Funami, M.; Amano, M.; Yamamoto, Y.; Aertgeerts, K.; Yano, J. A.H. Discovery of a 3-pyridylacetamide derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-IV) inhibitor. J. Med. Chem., 2011, 54(3), 831-850.
[37]
Gwaltney, S.L. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase IV. Curr. Top. Med. Chem., 2008, 8(17), 1545-1552.
[38]
M, Pal. Havale, S.H. Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes. Bioorg. Med. Chem., 2009, 17(5), 1783-1802.
[39]
Liu, Y.; Hu, Y.; Liu, T. Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: medicinal chemistry and preclinical aspects. Curr. Med. Chem., 2012, 19(23), 3982-3999.
[40]
Brandt, L.; Joossens, J.; Chen, X.; Maes, M.B.; Scharpe, S.; Lambeir, A.M. Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by vildagliptin ((2S)-[(3-hydroxyadamantan- 1-yl) amino] acetyl-pyrrolidine-2-carbonitrile). Biochem. Pharmacol., 2005, 70(1), 134-143.
[41]
Burkey, B.F.; Russell, M.; Wang, K.; Trappe, J.; Hughes, T.E. Vildagliptin displays slow tight-binding to dipeptidyl peptidase (DPP)-4, but not DPP-8 or DPP-9 (Abstract 0788). Diabetologia, 2006, 49, 477.
[43]
Xourgia, E.; Papazafiropoulou, A.K.; Karampousli, E.; Melidonis, A. DPP-4 Inhibitors vs. SGLT-2 Inhibitors. J. Ren. Med, 2017, 1(2-7), 1-7.
[44]
Liotta, L.A.; Kohn, E.C. The microenvironment of the tumour-host interface. Nature, 2001, 411, 375-379.
[45]
Vanhoof, G.; Goossens, F.; Meester, De. I.; Hendriks, D.; Scharpe, S. Proline motifs in peptides and their biological processing. FASEB J., 1995, 9(9), 736-744.
[46]
Šedo, A.; Malik, R. Dipeptidyl peptidase IV-like molecules: Homologous proteins or homologous activities? Biochim. Biophy. Acta (BBA)-. Protein Struct. Mol. Enzymol., 2001, 1550(2), 107-116.
[47]
Meester, D.I.; Durinx, C.; Bal, G.; Proost, P.; Struyf, S.; Goossens, F.; Augustyns, K.; Scharpe, S. Natural substrates of dipeptidyl peptidase IV. Adv. Experiment. Med. Biol., 2000, 477, 67-87.
[48]
Lambeir, A.M.; Durinx, C.; Proost, P.; Van Damme, J.; Scharpe, S.; Meester, D.I. Kinetic study of the processing by dipeptidyl-peptidase IV/CD26 of neuropeptides involved in pancreatic insulin secretion. FEBS Lett., 2001, 507(3), 327-330.
[49]
Mentlein, R. Dipeptidyl-peptidase IV (CD26)-role in the inactivation of regulatory peptides. Regulat. Pept., 1999, 85(1), 9-24.
[50]
Van. Damme, J. Struyf, S.; Wuyts, A.; Van.Coillie, E.; Menten, P.; Schols, D.; Sozzani, S.; Meester, De. I.; Proost, P. The role of CD26/DPP IV in chemokine processing. Chem. Immunol., 1999, 72, 42-56.
[51]
Dang, N.H.; Morimoto, C. CD26: An expanding role in immune regulation and cancer. Histol. Histopathol., 2002, 17(4), 1213-1226.
[52]
Iwata, S.; Morimoto, C. CD26/dipeptidyl peptidase IV in context. The different roles of a multifunctional ectoenzyme in malignant transformation. J. Exper. Med., 1999, 190(3), 301-306.
[53]
Kajiyama, H.; Kikkawa, F.; Suzuki, T.; Shibata, K.; Ino, K.; Mizutani, S. Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in ovarian carcinoma. Cancer Res., 2002, 62, 2753-2757.
[54]
Fiore, M.; de Filippo, S.; Pozzi, N.; Tamasi, S.; Pignata, C. Occupancy of dipeptidyl peptidase IV activates an associated tyrosine kinase and triggers an apoptotic signal in human hepatocarcinoma cells. Hepatology, 1998, 27(4), 934-942.
[55]
Ho, L.; Aytac, U.; Stephens, L.C.; Ohnuma, K.; Mills, G.B.; McKee, K.S.; Neumann, C.; LaPushin, R.; Cabanillas, F.; Abbruzzese, J.L.; Morimoto, C.; Dang, N.H. In vitro and in vivo antitumor effect of the anti-CD26 monoclonal antibody 1F7 on human CD30+ anaplastic large cell T-cell lymphoma Karpas 299. Clin. Cancer Res., 2001, 7(7), 2031-2040.
[56]
Gonzalez-Gronow, M.; Grenett, H.E.; Weber, M.R.; Gawdi, G.; Pizzo, S.V. Interaction of plasminogen with dipeptidyl peptidase IV initiates a signal transduction mechanism which regulates expression of matrix metalloproteinase-9 by prostate cancer cells. Biochem. J., 2001, 355(Pt 2), 397-407.
[57]
Ohnuma, K.; Munakata, Y.; Ishii, T.; Iwata, S.; Kobayashi, S.; Hosono, O.; Kawasaki, H.; Dang, N.H.; Morimoto, C. Soluble CD26/dipeptidyl peptidase IV induces T-cell proliferation through CD86 up-regulation on APCs. J. Immunol., 2001, 167(12), 6745-6755.
[58]
Scanlan, M.J.; Raj, B.K.; Calvo, B.; Garin-Chesa, P.; Sanz-Moncasi, M.P.; Healey, J.H.; Old, L.J.; Rettig, W.J. Molecular cloning of fibroblast activation protein. a member of the serine protease family selectively expressed in stromal fibroblasts of epithelial cancers. Proc. Nat. Acad. Sci. USA, 1994, 91(12), 5657-5661.
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