Discovery of Dengue Virus Inhibitors

doi:10.2174/0929867326666181204155336
摘要

到目前为止，市场上仍然没有获批准的抗登革热药物用于治疗登革热感染。虽然目前只有Dengvaxia这一获得许可的登革热疫苗，但据报道，它对登革热病毒血清型1和血清型2的保护效力低于血清型3和4。此外，据世卫组织说，血清阴性者在接受Dengvaxia疫苗接种后，住院和患严重登革热的风险增加。尽管如此，为寻找登革病毒抑制剂进行了各种研究。这些研究集中于登革病毒的结构(C、prM、E)和非结构蛋白(NS1、NS2A、NS2B、NS3、NS4A、NS4B和NS5)以及作为药物靶点的宿主因子。因此，本文提供了登革病毒抑制剂的最新发现，这些抑制剂只针对结构和非结构病毒蛋白作为药物靶点。
关键词: 药物发现，登革热病毒，病毒抑制剂，结构蛋白，非结构蛋白，药物靶标。
« Previous Next »
[1] 
Shepard, D.S.; Coudeville, L.; Halasa, Y.A.; Zambrano, B.; Dayan, G.H. Economic impact of dengue illness in the Americas. Am. J. Trop. Med. Hyg.,  2011, 84(2), 200-207.
[http://dx.doi.org/10.4269/ajtmh.2011.10-0503] [PMID:  21292885] 
[2] 
Shepard, D.S.; Undurraga, E.A.; Halasa, Y.A. Economic and disease burden of dengue in Southeast Asia. PLoS Negl. Trop. Dis.,  2013, 7(2), e2055.
[http://dx.doi.org/10.1371/journal.pntd.0002055] [PMID:  23437406] 
[3] 

World Health Organization Dengue: guidelines for diagnosis, treatment, prevention and control: new edition, 2009.
[4] 
Bhatt, S.; Gething, P.W.; Brady, O.J.; Messina, J.P.; Farlow, A.W.; Moyes, C.L.; Drake, J.M.; Brownstein, J.S.; Hoen, A.G.; Sankoh, O.; Myers, M.F.; George, D.B.; Jaenisch, T.; Wint, G.R.; Simmons, C.P.; Scott, T.W.; Farrar, J.J.; Hay, S.I. The global distribution and burden of dengue. Nature,  2013, 496(7446), 504-507.
[http://dx.doi.org/10.1038/nature12060] [PMID:  23563266] 
[5] 
Shepard, D.S.; Lees, R.; Ng, C.W.; Undurraga, E.A.; Halasa, Y.; Lum, L. burden of dengue in malaysia Report from a collaboration between universities and the ministry of health of malaysia., 2013.
[6] 
Gubler, D.; Kuno, G. Dengue and dengue hemorrhagic fever: its history and resurgence as a global public health problem. Dengue and dengue hemorrhagic fever; CAB international: London, United Kingdom, 1997, pp. 1-22.
[http://dx.doi.org/10.1016/B978-0-443-06668-9.50077-6] 
[7] 
Wilder-Smith, A.; Gubler, D.J. Geographic expansion of dengue: the impact of international travel. Med. Clin. North Am.,  2008, 92(6), 1377-1390, x..
[http://dx.doi.org/10.1016/j.mcna.2008.07.002] [PMID:  19061757] 
[8] 
Gubler, D.J. Dengue, urbanization and globalization: the unholy trinity of the 21st century. Trop. Med. Health,  2011, 39(4)(Suppl.), 3-11.
[http://dx.doi.org/10.2149/tmh.2011-S05] [PMID:  22500131] 
[9] 
Smith, C.E. The history of dengue in tropical Asia and its probable relationship to the mosquito Aedes aegypti. J. Trop. Med. Hyg.,  1956, 59(10), 243-251.
[PMID:  13368255] 
[10] 
Hirsch, A. Dengue, a comparatively new disease: its symptoms. handbook of geographical and historical pathology,; , 1883, 59, pp. 55-81.
[11] 
Ehrenkranz, N.J.; Ventura, A.K.; Cuadrado, R.R.; Pond, W.L.; Porter, J.E. Pandemic dengue in Caribbean countries and the southern United States--past, present and potential problems. N. Engl. J. Med.,  1971, 285(26), 1460-1469.
[http://dx.doi.org/10.1056/NEJM197112232852606] [PMID:  4941592] 
[12] 
Wang, E.; Ni, H.; Xu, R.; Barrett, A.D.; Watowich, S.J.; Gubler, D.J.; Weaver, S.C. Evolutionary relationships of endemic/epidemic and sylvatic dengue viruses. J. Virol.,  2000, 74(7), 3227-3234.
[http://dx.doi.org/10.1128/JVI.74.7.3227-3234.2000] [PMID:  10708439] 
[13] 
Holmes, E.C.; Twiddy, S.S. The origin, emergence and evolutionary genetics of dengue virus. Infect. Genet. Evol.,  2003, 3(1), 19-28.
[http://dx.doi.org/10.1016/S1567-1348(03)00004-2] [PMID:  12797969] 
[14] 
Weaver, S.C.; Barrett, A.D. Transmission cycles, host range, evolution and emergence of arboviral disease. Nat. Rev. Microbiol.,  2004, 2(10), 789-801.
[http://dx.doi.org/10.1038/nrmicro1006] [PMID:  15378043] 
[15] 
Midgley, C.M.; Bajwa-Joseph, M.; Vasanawathana, S.; Limpitikul, W.; Wills, B.; Flanagan, A.; Waiyaiya, E.; Tran, H.B.; Cowper, A.E.; Chotiyarnwong, P.; Grimes, J.M.; Yoksan, S.; Malasit, P.; Simmons, C.P.; Mongkolsapaya, J.; Screaton, G.R. An in-depth analysis of original antigenic sin in dengue virus infection. J. Virol.,  2011, 85(1), 410-421.
[http://dx.doi.org/10.1128/JVI.01826-10] [PMID:  20980526] 
[16] 
Halstead, S.B.; Rojanasuphot, S.; Sangkawibha, N. Original antigenic sin in dengue. Am. J. Trop. Med. Hyg.,  1983, 32(1), 154-156.
[http://dx.doi.org/10.4269/ajtmh.1983.32.154] [PMID:  6824120] 
[17] 
Halstead, S.B.; O’Rourke, E.J. Antibody-enhanced dengue virus infection in primate leukocytes. Nature,  1977, 265(5596), 739-741.
[http://dx.doi.org/10.1038/265739a0] [PMID:  404559] 
[18] 
Halstead, S.B.; O’Rourke, E.J. Dengue viruses and mononuclear phagocytes. I. Infection enhancement by non-neutralizing antibody. J. Exp. Med.,  1977, 146(1), 201-217.
[http://dx.doi.org/10.1084/jem.146.1.201] [PMID:  406347] 
[19] 
Goncalvez, A.P.; Engle, R.E.; St Claire, M.; Purcell, R.H.; Lai, C.-J. Monoclonal antibody-mediated enhancement of dengue virus infection in vitro and in vivo and strategies for prevention. Proc. Natl. Acad. Sci. USA,  2007, 104(22), 9422-9427.
[http://dx.doi.org/10.1073/pnas.0703498104] [PMID:  17517625] 
[20] 
Modis, Y.; Ogata, S.; Clements, D.; Harrison, S.C. A ligand-binding pocket in the dengue virus envelope glycoprotein. Proc. Natl. Acad. Sci. USA,  2003, 100(12), 6986-6991.
[http://dx.doi.org/10.1073/pnas.0832193100] [PMID:  12759475] 
[21] 
Modis, Y.; Ogata, S.; Clements, D.; Harrison, S.C. Structure of the dengue virus envelope protein after membrane fusion. Nature,  2004, 427(6972), 313-319.
[http://dx.doi.org/10.1038/nature02165] [PMID:  14737159] 
[22] 
Bressanelli, S.; Stiasny, K.; Allison, S.L.; Stura, E.A.; Duquerroy, S.; Lescar, J.; Heinz, F.X.; Rey, F.A. Structure of a flavivirus envelope glycoprotein in its low-pH-induced membrane fusion conformation. EMBO J.,  2004, 23(4), 728-738.
[http://dx.doi.org/10.1038/sj.emboj.7600064] [PMID:  14963486] 
[23] 
Cahour, A.; Falgout, B.; Lai, C.J. Cleavage of the dengue virus polyprotein at the NS3/NS4A and NS4B/NS5 junctions is mediated by viral protease NS2B-NS3, whereas NS4A/NS4B may be processed by a cellular protease. J. Virol.,  1992, 66(3), 1535-1542.
[http://dx.doi.org/10.1128/JVI.66.3.1535-1542.1992] [PMID:  1531368] 
[24] 
Amberg, S.M.; Nestorowicz, A.; McCourt, D.W.; Rice, C.M. NS2B-3 proteinase-mediated processing in the yellow fever virus structural region: in vitro and in vivo studies. J. Virol.,  1994, 68(6), 3794-3802.
[http://dx.doi.org/10.1128/JVI.68.6.3794-3802.1994] [PMID:  8189517] 
[25] 
Falgout, B.; Markoff, L. Evidence that flavivirus NS1-NS2A cleavage is mediated by a membrane-bound host protease in the endoplasmic reticulum. J. Virol.,  1995, 69(11), 7232-7243.
[http://dx.doi.org/10.1128/JVI.69.11.7232-7243.1995] [PMID:  7474145] 
[26] 
Falgout, B.; Pethel, M.; Zhang, Y.M.; Lai, C.J. Both nonstructural proteins NS2B and NS3 are required for the proteolytic processing of dengue virus nonstructural proteins. J. Virol.,  1991, 65(5), 2467-2475.
[http://dx.doi.org/10.1128/JVI.65.5.2467-2475.1991] [PMID:  2016768] 
[27] 
Uchil, P.D.; Satchidanandam, V. Architecture of the flaviviral replication complex. Protease, nuclease, and detergents reveal encasement within double-layered membrane compartments. J. Biol. Chem.,  2003, 278(27), 24388-24398.
[http://dx.doi.org/10.1074/jbc.M301717200] [PMID:  12700232] 
[28] 
Jiang, L.; Yao, H.; Duan, X.; Lu, X.; Liu, Y. Polypyrimidine tract-binding protein influences negative strand RNA synthesis of dengue virus. Biochem. Biophys. Res. Commun.,  2009, 385(2), 187-192.
[http://dx.doi.org/10.1016/j.bbrc.2009.05.036] [PMID:  19450550] 
[29] 
Bartholomeusz, A.I.; Wright, P.J. Synthesis of dengue virus RNA in vitro: initiation and the involvement of proteins NS3 and NS5. Arch. Virol.,  1993, 128(1-2), 111-121.
[http://dx.doi.org/10.1007/BF01309792] [PMID:  8418788] 
[30] 
Li, H.; Clum, S.; You, S.; Ebner, K.E.; Padmanabhan, R. The serine protease and RNA-stimulated nucleoside triphosphatase and RNA helicase functional domains of dengue virus type 2 NS3 converge within a region of 20 amino acids. J. Virol.,  1999, 73(4), 3108-3116.
[http://dx.doi.org/10.1128/JVI.73.4.3108-3116.1999] [PMID:  10074162] 
[31] 
Egloff, M.P.; Benarroch, D.; Selisko, B.; Romette, J.L.; Canard, B. An RNA cap (nucleoside-2′-O-)-methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization. EMBO J.,  2002, 21(11), 2757-2768.
[http://dx.doi.org/10.1093/emboj/21.11.2757] [PMID:  12032088] 
[32] 
Issur, M.; Geiss, B.J.; Bougie, I.; Picard-Jean, F.; Despins, S.; Mayette, J.; Hobdey, S.E.; Bisaillon, M. The flavivirus NS5 protein is a true RNA guanylyltransferase that catalyzes a two-step reaction to form the RNA cap structure. RNA,  2009, 15(12), 2340-2350.
[http://dx.doi.org/10.1261/rna.1609709] [PMID:  19850911] 
[33] 
Yu, I-M.; Zhang, W.; Holdaway, H.A.; Li, L.; Kostyuchenko, V.A.; Chipman, P.R.; Kuhn, R.J.; Rossmann, M.G.; Chen, J. Structure of the immature dengue virus at low pH primes proteolytic maturation. Science,  2008, 319(5871), 1834-1837.
[http://dx.doi.org/10.1126/science.1153264] [PMID:  18369148] 
[34] 
Heinz, F. X.; Allison, S. L. Structures and mechanisms in flavivirus fusion., 2000.
[http://dx.doi.org/10.1016/s0065-3527(00)55005-2] 
[35] 
Yu, I.M.; Holdaway, H.A.; Chipman, P.R.; Kuhn, R.J.; Rossmann, M.G.; Chen, J. Association of the pr peptides with dengue virus at acidic pH blocks membrane fusion. J. Virol.,  2009, 83(23), 12101-12107.
[http://dx.doi.org/10.1128/JVI.01637-09] [PMID:  19759134] 
[36] 
Simmons, C.P.; Farrar, J.J.; Nguyen, V.; Wills, B. Dengue. N. Engl. J. Med.,  2012, 366(15), 1423-1432.
[http://dx.doi.org/10.1056/NEJMra1110265] [PMID:  22494122] 
[37] 
Organization, W.H. Research, S. P. f.; Diseases, T. i. T.; Diseases, W. H. O. D. o. C. o. N. T.; Epidemic, W. H. O.; Alert, P., Dengue: guidelines for diagnosis, treatment, prevention and control; World Health Organization, 2009. 
[38] 
Sanofi, P. Sanofi pasteur dengue vaccine approved in Costa Rica., http://www.sanofipasteur.ca/node/49201
[39] 
Villar, L.; Dayan, G.H.; Arredondo-García, J.L.; Rivera, D.M.; Cunha, R.; Deseda, C.; Reynales, H.; Costa, M.S.; Morales-Ramírez, J.O.; Carrasquilla, G.; Rey, L.C.; Dietze, R.; Luz, K.; Rivas, E.; Miranda Montoya, M.C.; Cortés Supelano, M.; Zambrano, B.; Langevin, E.; Boaz, M.; Tornieporth, N.; Saville, M.; Noriega, F.; Group, C.Y.D.S. CYD15 Study Group Efficacy of a tetravalent dengue vaccine in children in Latin America. N. Engl. J. Med.,  2015, 372(2), 113-123.
[http://dx.doi.org/10.1056/NEJMoa1411037] [PMID:  25365753] 
[40] 
Capeding, M.R.; Tran, N.H.; Hadinegoro, S.R.; Ismail, H.I.; Chotpitayasunondh, T.; Chua, M.N.; Luong, C.Q.; Rusmil, K.; Wirawan, D.N.; Nallusamy, R.; Pitisuttithum, P.; Thisyakorn, U.; Yoon, I.K.; van der Vliet, D.; Langevin, E.; Laot, T.; Hutagalung, Y.; Frago, C.; Boaz, M.; Wartel, T.A.; Tornieporth, N.G.; Saville, M.; Bouckenooghe, A.; Group, C.Y.D.S. CYD14 Study Group. Clinical efficacy and safety of a novel tetravalent dengue vaccine in healthy children in Asia: a phase 3, randomised, observer-masked, placebo-controlled trial. Lancet,  2014, 384(9951), 1358-1365.
[http://dx.doi.org/10.1016/S0140-6736(14)61060-6] [PMID:  25018116] 
[41] 

CNN Philippines Staff TIMELINE. The Dengvaxia controversy., http://cnnphilippines.com/news/2017/12/09/The-Dengvaxia-controversy.html2018
[42] 
 w.h.o. revised sage recommendation on use of dengue vaccine,  http://www.who.int/immunization/diseases/dengue/revised_SAGE_recommendations_dengue_vaccines_ apr2018/en/ (accessed date: 1st june 2018).
[43] 
Behnam, M.A.; Nitsche, C.; Boldescu, V.; Klein, C.D. the medicinal chemistry of dengue virus. J. Med. Chem.,  2016, 59(12), 5622-5649.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01653] [PMID:  26771861] 
[44] 
García, L.L.; Padilla, L.; Castaño, J.C. Inhibitors compounds of the flavivirus replication process. Virol. J.,  2017, 14(1), 95.
[http://dx.doi.org/10.1186/s12985-017-0761-1] [PMID:  28506240] 
[45] 
Lim, S.P.; Noble, C.G.; Shi, P.Y. The dengue virus NS5 protein as a target for drug discovery. Antiviral Res.,  2015, 119, 57-67.
[http://dx.doi.org/10.1016/j.antiviral.2015.04.010] [PMID:  25912817] 
[46] 
Lim, S.P.; Wang, Q.Y.; Noble, C.G.; Chen, Y.L.; Dong, H.; Zou, B.; Yokokawa, F.; Nilar, S.; Smith, P.; Beer, D.; Lescar, J.; Shi, P.Y. Ten years of dengue drug discovery: progress and prospects. Antiviral Res.,  2013, 100(2), 500-519.
[http://dx.doi.org/10.1016/j.antiviral.2013.09.013] [PMID:  24076358] 
[47] 
Noble, C.G.; Chen, Y.L.; Dong, H.; Gu, F.; Lim, S.P.; Schul, W.; Wang, Q.Y.; Shi, P.Y. Strategies for development of Dengue virus inhibitors. Antiviral Res.,  2010, 85(3), 450-462.
[http://dx.doi.org/10.1016/j.antiviral.2009.12.011] [PMID:  20060421] 
[48] 
Noble, C.G.; Shi, P.Y. Structural biology of dengue virus enzymes: towards rational design of therapeutics. Antiviral Res.,  2012, 96(2), 115-126.
[http://dx.doi.org/10.1016/j.antiviral.2012.09.007] [PMID:  22995600] 
[49] 
Wangikar, P.; Martis, E.A.F.; Ambre, P.K.; Nandan, S.; Coutinho, E.C. Update on methyltransferase inhibitors of the dengue virus and further scope in the field. Journal of Infectious Disease and Pathology,  2016, 1(1)
[50] 
Cruz-Oliveira, C.; Freire, J.M.; Conceição, T.M.; Higa, L.M.; Castanho, M.A.; Da Poian, A.T. Receptors and routes of dengue virus entry into the host cells. FEMS Microbiol. Rev.,  2015, 39(2), 155-170.
[http://dx.doi.org/10.1093/femsre/fuu004] [PMID:  25725010] 
[51] 
Ma, L.; Jones, C.T.; Groesch, T.D.; Kuhn, R.J.; Post, C.B. Solution structure of dengue virus capsid protein reveals another fold. Proc. Natl. Acad. Sci. USA,  2004, 101(10), 3414-3419.
[http://dx.doi.org/10.1073/pnas.0305892101] [PMID:  14993605] 
[52] 
Byk, L.A.; Gamarnik, A.V. Properties and functions of the dengue virus capsid protein. Annu. Rev. Virol.,  2016, 3(1), 263-281.
[http://dx.doi.org/10.1146/annurev-virology-110615-042334] [PMID:  27501261] 
[53] 
Klumpp, K.; Crépin, T. Capsid proteins of enveloped viruses as antiviral drug targets. Curr. Opin. Virol.,  2014, 5, 63-71.
[http://dx.doi.org/10.1016/j.coviro.2014.02.002] [PMID:  24607800] 
[54] 
Byrd, C.M.; Dai, D.; Grosenbach, D.W.; Berhanu, A.; Jones, K.F.; Cardwell, K.B.; Schneider, C.; Wineinger, K.A.; Page, J.M.; Harver, C.; Stavale, E.; Tyavanagimatt, S.; Stone, M.A.; Bartenschlager, R.; Scaturro, P.; Hruby, D.E.; Jordan, R. A novel inhibitor of dengue virus replication that targets the capsid protein. Antimicrob. Agents Chemother.,  2013, 57(1), 15-25.
[http://dx.doi.org/10.1128/AAC.01429-12] [PMID:  23070172] 
[55] 
Scaturro, P.; Trist, I.M.; Paul, D.; Kumar, A.; Acosta, E.G.; Byrd, C.M.; Jordan, R.; Brancale, A.; Bartenschlager, R. Characterization of the mode of action of a potent dengue virus capsid inhibitor. J. Virol.,  2014, 88(19), 11540-11555.
[http://dx.doi.org/10.1128/JVI.01745-14] [PMID:  25056895] 
[56] 
Martins, I.C.; Gomes-Neto, F.; Faustino, A.F.; Carvalho, F.A.; Carneiro, F.A.; Bozza, P.T.; Mohana-Borges, R.; Castanho, M.A.; Almeida, F.C.; Santos, N.C.; Da Poian, A.T. The disordered N-terminal region of dengue virus capsid protein contains a lipid-droplet-binding motif. Biochem. J.,  2012, 444(3), 405-415.
[http://dx.doi.org/10.1042/BJ20112219] [PMID:  22428600] 
[57] 
Li, L.; Lok, S-M.; Yu, I-M.; Zhang, Y.; Kuhn, R.J.; Chen, J.; Rossmann, M.G. The flavivirus precursor membrane-envelope protein complex: structure and maturation. Science,  2008, 319(5871), 1830-1834.
[http://dx.doi.org/10.1126/science.1153263] [PMID:  18369147] 
[58] 
Zhang, X.; Ge, P.; Yu, X.; Brannan, J.M.; Bi, G.; Zhang, Q.; Schein, S.; Zhou, Z.H. Cryo-EM structure of the mature dengue virus at 3.5-Å resolution. Nat. Struct. Mol. Biol.,  2013, 20(1), 105-110.
[http://dx.doi.org/10.1038/nsmb.2463] [PMID:  23241927] 
[59] 
Panya, A.; Sawasdee, N.; Junking, M.; Srisawat, C.; Choowongkomon, K.; Yenchitsomanus, P.T. A peptide inhibitor derived from the conserved ectodomain region of DENV membrane (M) protein with activity against dengue virus infection. Chem. Biol. Drug Des.,  2015, 86(5), 1093-1104.
[http://dx.doi.org/10.1111/cbdd.12576] [PMID:  25891143] 
[60] 
Zheng, A.; Umashankar, M.; Kielian, M. In vitro and in vivo studies identify important features of dengue virus pr-E protein interactions. PLoS Pathog.,  2010, 6(10), e1001157.
[http://dx.doi.org/10.1371/journal.ppat.1001157] [PMID:  20975939] 
[61] 
Mukhopadhyay, S.; Kuhn, R.J.; Rossmann, M.G. A structural perspective of the flavivirus life cycle. Nat. Rev. Microbiol.,  2005, 3(1), 13-22.
[http://dx.doi.org/10.1038/nrmicro1067] [PMID:  15608696] 
[62] 
Cambi, A.; de Lange, F.; van Maarseveen, N.M.; Nijhuis, M.; Joosten, B.; van Dijk, E.M.; de Bakker, B.I.; Fransen, J.A.; Bovee-Geurts, P.H.; van Leeuwen, F.N.; Van Hulst, N.F.; Figdor, C.G. Microdomains of the C-type lectin DC-SIGN are portals for virus entry into dendritic cells. J. Cell Biol.,  2004, 164(1), 145-155.
[http://dx.doi.org/10.1083/jcb.200306112] [PMID:  14709546] 
[63] 
Tassaneetrithep, B.; Burgess, T.H.; Granelli-Piperno, A.; Trumpfheller, C.; Finke, J.; Sun, W.; Eller, M.A.; Pattanapanyasat, K.; Sarasombath, S.; Birx, D.L.; Steinman, R.M.; Schlesinger, S.; Marovich, M.A. DC-SIGN (CD209) mediates dengue virus infection of human dendritic cells. J. Exp. Med.,  2003, 197(7), 823-829.
[http://dx.doi.org/10.1084/jem.20021840] [PMID:  12682107] 
[64] 
Dejnirattisai, W.; Wongwiwat, W.; Supasa, S.; Zhang, X.; Dai, X.; Rouvinski, A.; Jumnainsong, A.; Edwards, C.; Quyen, N.T.H.; Duangchinda, T.; Grimes, J.M.; Tsai, W.Y.; Lai, C.Y.; Wang, W.K.; Malasit, P.; Farrar, J.; Simmons, C.P.; Zhou, Z.H.; Rey, F.A.; Mongkolsapaya, J.; Screaton, G.R. A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus. Nat. Immunol.,  2015, 16(2), 170-177.
[http://dx.doi.org/10.1038/ni.3058] [PMID:  25501631] 
[65] 
Smith, S.A.; de Alwis, A.R.; Kose, N.; Harris, E.; Ibarra, K.D.; Kahle, K.M.; Pfaff, J.M.; Xiang, X.; Doranz, B.J.; de Silva, A.M.; Austin, S.K.; Sukupolvi-Petty, S.; Diamond, M.S.; Crowe, J.E. Jr. The potent and broadly neutralizing human dengue virus-specific monoclonal antibody 1C19 reveals a unique cross-reactive epitope on the bc loop of domain II of the envelope protein. MBio,  2013, 4(6), e00873-e13.
[http://dx.doi.org/10.1128/mBio.00873-13] [PMID:  24255124] 
[66] 
Alen, M.M.; Schols, D. Dengue virus entry as target for antiviral therapy. J. Trop. Med.,  2012, 2012, 628475.
[http://dx.doi.org/10.1155/2012/628475] [PMID:  22529868] 
[67] 
Sayce, A.C.; Miller, J.L.; Zitzmann, N. Targeting a host process as an antiviral approach against dengue virus. Trends Microbiol.,  2010, 18(7), 323-330.
[http://dx.doi.org/10.1016/j.tim.2010.04.003] [PMID:  20452219] 
[68] 
Yap, S.S.L.; Nguyen-Khuong, T.; Rudd, P.M.; Alonso, S. Dengue virus glycosylation: what do we know? Front. Microbiol.,  2017, 8, 1415.
[http://dx.doi.org/10.3389/fmicb.2017.01415] [PMID:  28791003] 
[69] 
Fibriansah, G.; Ng, T.S.; Kostyuchenko, V.A.; Lee, J.; Lee, S.; Wang, J.; Lok, S.M. Structural changes in dengue virus when exposed to a temperature of 37°C. J. Virol.,  2013, 87(13), 7585-7592.
[http://dx.doi.org/10.1128/JVI.00757-13] [PMID:  23637405] 
[70] 
Yang, J.M.; Chen, Y.F.; Tu, Y.Y.; Yen, K.R.; Yang, Y.L. Combinatorial computational approaches to identify tetracycline derivatives as flavivirus inhibitors. PLoS One,  2007, 2(5), e428.
[http://dx.doi.org/10.1371/journal.pone.0000428] [PMID:  17502914] 
[71] 
Zhou, Z.; Khaliq, M.; Suk, J.E.; Patkar, C.; Li, L.; Kuhn, R.J.; Post, C.B. Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. ACS Chem. Biol.,  2008, 3(12), 765-775.
[http://dx.doi.org/10.1021/cb800176t] [PMID:  19053243] 
[72] 
Li, Z.; Khaliq, M.; Zhou, Z.; Post, C.B.; Kuhn, R.J.; Cushman, M. Design, synthesis, and biological evaluation of antiviral agents targeting flavivirus envelope proteins. J. Med. Chem.,  2008, 51(15), 4660-4671.
[http://dx.doi.org/10.1021/jm800412d] [PMID:  18610998] 
[73] 
Kampmann, T.; Yennamalli, R.; Campbell, P.; Stoermer, M.J.; Fairlie, D.P.; Kobe, B.; Young, P.R. In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. Antiviral Res.,  2009, 84(3), 234-241.
[http://dx.doi.org/10.1016/j.antiviral.2009.09.007] [PMID:  19781577] 
[74] 
Yennamalli, R.; Subbarao, N.; Kampmann, T.; McGeary, R.P.; Young, P.R.; Kobe, B. Identification of novel target sites and an inhibitor of the dengue virus E protein. J. Comput. Aided Mol. Des.,  2009, 23(6), 333-341.
[http://dx.doi.org/10.1007/s10822-009-9263-6] [PMID:  19241120] 
[75] 
Wang, Q.Y.; Patel, S.J.; Vangrevelinghe, E.; Xu, H.Y.; Rao, R.; Jaber, D.; Schul, W.; Gu, F.; Heudi, O.; Ma, N.L.; Poh, M.K.; Phong, W.Y.; Keller, T.H.; Jacoby, E.; Vasudevan, S.G. A small-molecule dengue virus entry inhibitor. Antimicrob. Agents Chemother.,  2009, 53(5), 1823-1831.
[http://dx.doi.org/10.1128/AAC.01148-08] [PMID:  19223625] 
[76] 
Poh, M.K.; Yip, A.; Zhang, S.; Priestle, J.P.; Ma, N.L.; Smit, J.M.; Wilschut, J.; Shi, P.Y.; Wenk, M.R.; Schul, W. A small molecule fusion inhibitor of dengue virus. Antiviral Res.,  2009, 84(3), 260-266.
[http://dx.doi.org/10.1016/j.antiviral.2009.09.011] [PMID:  19800368] 
[77] 
Schmidt, A.G.; Lee, K.; Yang, P.L.; Harrison, S.C. Small-molecule inhibitors of dengue-virus entry. PLoS Pathog.,  2012, 8(4), e1002627.
[http://dx.doi.org/10.1371/journal.ppat.1002627] [PMID:  22496653] 
[78] 
Clark, M.J.; Miduturu, C.; Schmidt, A.G.; Zhu, X.; Pitts, J.D.; Wang, J.; Potisopon, S.; Zhang, J.; Wojciechowski, A.; Hann Chu, J.J.; Gray, N.S.; Yang, P.L. gnf-2 inhibits dengue virus by targeting Abl kinases and the viral E protein. Cell Chem. Biol.,  2016, 23(4), 443-452.
[http://dx.doi.org/10.1016/j.chembiol.2016.03.010] [PMID:  27105280] 
[79] 
Abdul Ahmad, S.A.; Palanisamy, U.D.; Tejo, B.A.; Chew, M.F.; Tham, H.W.; Syed Hassan, S. Geraniin extracted from the rind of Nephelium lappaceum binds to dengue virus type-2 envelope protein and inhibits early stage of virus replication. Virol. J.,  2017, 14(1), 229.
[http://dx.doi.org/10.1186/s12985-017-0895-1] [PMID:  29162124] 
[80] 
Kaptein, S.J.; De Burghgraeve, T.; Froeyen, M.; Pastorino, B.; Alen, M.M.; Mondotte, J.A.; Herdewijn, P.; Jacobs, M.; de Lamballerie, X.; Schols, D.; Gamarnik, A.V.; Sztaricskai, F.; Neyts, J. A derivate of the antibiotic doxorubicin is a selective inhibitor of dengue and yellow fever virus replication in vitro. Antimicrob. Agents Chemother.,  2010, 54(12), 5269-5280.
[http://dx.doi.org/10.1128/AAC.00686-10] [PMID:  20837762] 
[81] 
De Burghgraeve, T.; Kaptein, S.J.; Ayala-Nunez, N.V.; Mondotte, J.A.; Pastorino, B.; Printsevskaya, S.S.; de Lamballerie, X.; Jacobs, M.; Preobrazhenskaya, M.; Gamarnik, A.V.; Smit, J.M.; Neyts, J. An analogue of the antibiotic teicoplanin prevents flavivirus entry in vitro. PLoS One,  2012, 7(5), e37244.
[http://dx.doi.org/10.1371/journal.pone.0037244] [PMID:  22624001] 
[82] 
Hrobowski, Y.M.; Garry, R.F.; Michael, S.F. Peptide inhibitors of dengue virus and West Nile virus infectivity. Virol. J.,  2005, 2, 49.
[http://dx.doi.org/10.1186/1743-422X-2-49] [PMID:  15927084] 
[83] 
White, S.H.; Wimley, W.C. Membrane protein folding and stability: physical principles. Annu. Rev. Biophys. Biomol. Struct.,  1999, 28(1), 319-365.
[http://dx.doi.org/10.1146/annurev.biophys.28.1.319] [PMID:  10410805] 
[84] 
Allison, S.L.; Stiasny, K.; Stadler, K.; Mandl, C.W.; Heinz, F.X. Mapping of functional elements in the stem-anchor region of tick-borne encephalitis virus envelope protein E. J. Virol.,  1999, 73(7), 5605-5612.
[http://dx.doi.org/10.1128/JVI.73.7.5605-5612.1999] [PMID:  10364309] 
[85] 
Costin, J.M.; Jenwitheesuk, E.; Lok, S.M.; Hunsperger, E.; Conrads, K.A.; Fontaine, K.A.; Rees, C.R.; Rossmann, M.G.; Isern, S.; Samudrala, R.; Michael, S.F. Structural optimization and de novo design of dengue virus entry inhibitory peptides. PLoS Negl. Trop. Dis.,  2010, 4(6)e721
[http://dx.doi.org/10.1371/journal.pntd.0000721] [PMID:  20582308] 
[86] 
Samudrala, R.; Moult, J. An all-atom distance-dependent conditional probability discriminatory function for protein structure prediction. J. Mol. Biol.,  1998, 275(5), 895-916.
[http://dx.doi.org/10.1006/jmbi.1997.1479] [PMID:  9480776] 
[87] 
Lok, S.M.; Costin, J.M.; Hrobowski, Y.M.; Hoffmann, A.R.; Rowe, D.K.; Kukkaro, P.; Holdaway, H.; Chipman, P.; Fontaine, K.A.; Holbrook, M.R.; Garry, R.F.; Kostyuchenko, V.; Wimley, W.C.; Isern, S.; Rossmann, M.G.; Michael, S.F. Release of dengue virus genome induced by a peptide inhibitor. PLoS One,  2012, 7(11), e50995.
[http://dx.doi.org/10.1371/journal.pone.0050995] [PMID:  23226444] 
[88] 
Nicholson, C.O.; Costin, J.M.; Rowe, D.K.; Lin, L.; Jenwitheesuk, E.; Samudrala, R.; Isern, S.; Michael, S.F. Viral entry inhibitors block dengue antibody-dependent enhancement in vitro. Antiviral Res.,  2011, 89(1), 71-74.
[http://dx.doi.org/10.1016/j.antiviral.2010.11.008] [PMID:  21093488] 
[89] 
Xu, Y.; Rahman, N.A.; Othman, R.; Hu, P.; Huang, M. Computational identification of self-inhibitory peptides from envelope proteins. Proteins,  2012, 80(9), 2154-2168.
[http://dx.doi.org/10.1002/prot.24105] [PMID:  22544824] 
[90] 
Schmidt, A.G.; Yang, P.L.; Harrison, S.C. Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog.,  2010, 6(4), e1000851.
[http://dx.doi.org/10.1371/journal.ppat.1000851] [PMID:  20386713] 
[91] 
Schmidt, A.G.; Yang, P.L.; Harrison, S.C. Peptide inhibitors of flavivirus entry derived from the E protein stem. J. Virol.,  2010, 84(24), 12549-12554.
[http://dx.doi.org/10.1128/JVI.01440-10] [PMID:  20881042] 
[92] 
Hung, J.J.; Hsieh, M.T.; Young, M.J.; Kao, C.L.; King, C.C.; Chang, W. An external loop region of domain III of dengue virus type 2 envelope protein is involved in serotype-specific binding to mosquito but not mammalian cells. J. Virol.,  2004, 78(1), 378-388.
[http://dx.doi.org/10.1128/JVI.78.1.378-388.2004] [PMID:  14671119] 
[93] 
Mazumder, R.; Hu, Z.Z.; Vinayaka, C.R.; Sagripanti, J.L.; Frost, S.D.; Kosakovsky Pond, S.L.; Wu, C.H. Computational analysis and identification of amino acid sites in dengue E proteins relevant to development of diagnostics and vaccines. Virus Genes,  2007, 35(2), 175-186.
[http://dx.doi.org/10.1007/s11262-007-0103-2] [PMID:  17508277] 
[94] 
Hiramatsu, K.; Tadano, M.; Men, R.; Lai, C.J. Mutational analysis of a neutralization epitope on the dengue type 2 virus (DEN2) envelope protein: monoclonal antibody resistant DEN2/DEN4 chimeras exhibit reduced mouse neurovirulence. Virology,  1996, 224(2), 437-445.
[http://dx.doi.org/10.1006/viro.1996.0550] [PMID:  8874504] 
[95] 
Alhoot, M.A.; Rathinam, A.K.; Wang, S.M.; Manikam, R.; Sekaran, S.D. Inhibition of dengue virus entry into target cells using synthetic antiviral peptides. Int. J. Med. Sci.,  2013, 10(6), 719-729.
[http://dx.doi.org/10.7150/ijms.5037] [PMID:  23630436] 
[96] 
Panya, A.; Bangphoomi, K.; Choowongkomon, K.; Yenchitsomanus, P.T. Peptide inhibitors against dengue virus infection. Chem. Biol. Drug Des.,  2014, 84(2), 148-157.
[http://dx.doi.org/10.1111/cbdd.12309] [PMID:  24612829] 
[97] 
Rentzsch, R.; Renard, B.Y. Docking small peptides remains a great challenge: an assessment using Auto Dock Vina. Brief. Bioinform.,  2015, 16(6), 1045-1056.
[http://dx.doi.org/10.1093/bib/bbv008] [PMID:  25900849] 
[98] 
de la Guardia, C.; Quijada, M.; Lleonart, R. Phage-displayed peptides selected to bind envelope glycoprotein show antiviral activity against dengue virus serotype 2. Adv. Virol.,  2017, 2017, 1827341.
[http://dx.doi.org/10.1155/2017/1827341] [PMID:  29081802] 
[99] 
Chew, M.F.; Tham, H.W.; Rajik, M.; Sharifah, S.H. Anti-dengue virus serotype 2 activity and mode of action of a novel peptide. J. Appl. Microbiol.,  2015, 119(4), 1170-1180.
[http://dx.doi.org/10.1111/jam.12921] [PMID:  26248692] 
[100] 
De Clercq, E.; Li, G. Approved antiviral drugs over the past 50 years. Clin. Microbiol. Rev.,  2016, 29(3), 695-747.
[http://dx.doi.org/10.1128/CMR.00102-15] [PMID:  27281742] 
[101] 
Lalezari, J.P.; Henry, K.; O’Hearn, M.; Montaner, J.S.; Piliero, P.J.; Trottier, B.; Walmsley, S.; Cohen, C.; Kuritzkes, D.R.; Eron, J.J. Jr.; Chung, J.; DeMasi, R.; Donatacci, L.; Drobnes, C.; Delehanty, J.; Salgo, M.; Group, T.S. TORO 1 Study Group. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. N. Engl. J. Med.,  2003, 348(22), 2175-2185.
[http://dx.doi.org/10.1056/NEJMoa035026] [PMID:  12637625] 
[102] 
Pugach, P.; Ketas, T.J.; Michael, E.; Moore, J.P. Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors. Virology,  2008, 377(2), 401-407.
[http://dx.doi.org/10.1016/j.virol.2008.04.032] [PMID:  18519143] 
[103] 
Volz, T.; Allweiss, L. Ben MBarek, M.; Warlich, M.; Lohse, A.W.; Pollok, J.M.; Alexandrov, A.; Urban, S.; Petersen, J.; Lütgehet-mann, M.; Dandri, M. The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J. Hepatol.,  2013, 58(5), 861-867.
[http://dx.doi.org/10.1016/j.jhep.2012.12.008] [PMID:  23246506] 
[104] 
Lindenbach, B.; Thiel, H. J.; Rice, C. M. flaviviridae: the viruses and their replication, 2007.
[105] 
Edeling, M.A.; Diamond, M.S.; Fremont, D.H. Structural basis of Flavivirus NS1 assembly and antibody recognition. Proc. Natl. Acad. Sci. USA,  2014, 111(11), 4285-4290.
[http://dx.doi.org/10.1073/pnas.1322036111] [PMID:  24594604] 
[106] 
Lindenbach, B.D.; Rice, C.M. trans-Complementation of yellow fever virus NS1 reveals a role in early RNA replication. J. Virol.,  1997, 71(12), 9608-9617.
[http://dx.doi.org/10.1128/JVI.71.12.9608-9617.1997] [PMID:  9371625] 
[107] 
Somnuke, P.; Hauhart, R.E.; Atkinson, J.P.; Diamond, M.S.; Avirutnan, P. N-linked glycosylation of dengue virus NS1 protein modulates secretion, cell-surface expression, hexamer stability, and interactions with human complement. Virology,  2011, 413(2), 253-264.
[http://dx.doi.org/10.1016/j.virol.2011.02.022] [PMID:  21429549] 
[108] 
Muller, D.A.; Young, P.R. The flavivirus NS1 protein: molecular and structural biology, immunology, role in pathogenesis and application as a diagnostic biomarker. Antiviral Res.,  2013, 98(2), 192-208.
[http://dx.doi.org/10.1016/j.antiviral.2013.03.008] [PMID:  23523765] 
[109] 
Winkler, G.; Maxwell, S.E.; Ruemmler, C.; Stollar, V. Newly synthesized dengue-2 virus nonstructural protein NS1 is a soluble protein but becomes partially hydrophobic and membrane-associated after dimerization. Virology,  1989, 171(1), 302-305.
[http://dx.doi.org/10.1016/0042-6822(89)90544-8] [PMID:  2525840] 
[110] 
Flamand, M.; Megret, F.; Mathieu, M.; Lepault, J.; Rey, F.A.; Deubel, V. Dengue virus type 1 nonstructural glycoprotein NS1 is secreted from mammalian cells as a soluble hexamer in a glycosylation-dependent fashion. J. Virol.,  1999, 73(7), 6104-6110.
[http://dx.doi.org/10.1128/JVI.73.7.6104-6110.1999] [PMID:  10364366] 
[111] 
Crabtree, M.B.; Kinney, R.M.; Miller, B.R. Deglycosylation of the NS1 protein of dengue 2 virus, strain 16681: construction and characterization of mutant viruses. Arch. Virol.,  2005, 150(4), 771-786.
[http://dx.doi.org/10.1007/s00705-004-0430-8] [PMID:  15592895] 
[112] 
Pryor, M.J.; Wright, P.J. Glycosylation mutants of dengue virus NS1 protein. J. Gen. Virol.,  1994, 75(Pt 5), 1183-1187.
[http://dx.doi.org/10.1099/0022-1317-75-5-1183] [PMID:  8176380] 
[113] 
Tajima, S.; Takasaki, T.; Kurane, I. Characterization of Asn130-to-Ala mutant of dengue type 1 virus NS1 protein. Virus Genes,  2008, 36(2), 323-329.
[http://dx.doi.org/10.1007/s11262-008-0211-7] [PMID:  18288598] 
[114] 
Lindenbach, B.D.; Rice, C.M. Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function. J. Virol.,  1999, 73(6), 4611-4621.
[http://dx.doi.org/10.1128/JVI.73.6.4611-4621.1999] [PMID:  10233920] 
[115] 
Youn, S.; Li, T.; McCune, B.T.; Edeling, M.A.; Fremont, D.H.; Cristea, I.M.; Diamond, M.S. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J. Virol.,  2012, 86(13), 7360-7371.
[http://dx.doi.org/10.1128/JVI.00157-12] [PMID:  22553322] 
[116] 
Avirutnan, P.; Punyadee, N.; Noisakran, S.; Komoltri, C.; Thiemmeca, S.; Auethavornanan, K.; Jairungsri, A.; Kanlaya, R.; Tangthawornchaikul, N.; Puttikhunt, C.; Pattanakitsakul, S.N.; Yenchitsomanus, P.T.; Mongkolsapaya, J.; Kasinrerk, W.; Sittisombut, N.; Husmann, M.; Blettner, M.; Vasanawathana, S.; Bhakdi, S.; Malasit, P. Vascular leakage in severe dengue virus infections: a potential role for the nonstructural viral protein NS1 and complement. J. Infect. Dis.,  2006, 193(8), 1078-1088.
[http://dx.doi.org/10.1086/500949] [PMID:  16544248] 
[117] 
Rathore, A.P.; Paradkar, P.N.; Watanabe, S.; Tan, K.H.; Sung, C.; Connolly, J.E.; Low, J.; Ooi, E.E.; Vasudevan, S.G. Celgosivir treatment misfolds dengue virus NS1 protein, induces cellular pro-survival genes and protects against lethal challenge mouse model. Antiviral Res.,  2011, 92(3), 453-460.
[http://dx.doi.org/10.1016/j.antiviral.2011.10.002] [PMID:  22020302] 
[118] 
Akey, D.L.; Brown, W.C.; Dutta, S.; Konwerski, J.; Jose, J.; Jurkiw, T.J.; DelProposto, J.; Ogata, C.M.; Skiniotis, G.; Kuhn, R.J.; Smith, J.L. Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system. Science,  2014, 343(6173), 881-885.
[http://dx.doi.org/10.1126/science.1247749] [PMID:  24505133] 
[119] 
Xie, X.; Gayen, S.; Kang, C.; Yuan, Z.; Shi, P.Y. Membrane topology and function of dengue virus NS2A protein. J. Virol.,  2013, 87(8), 4609-4622.
[http://dx.doi.org/10.1128/JVI.02424-12] [PMID:  23408612] 
[120] 
Leung, J.Y.; Pijlman, G.P.; Kondratieva, N.; Hyde, J.; Mackenzie, J.M.; Khromykh, A.A. Role of nonstructural protein NS2A in flavivirus assembly. J. Virol.,  2008, 82(10), 4731-4741.
[http://dx.doi.org/10.1128/JVI.00002-08] [PMID:  18337583] 
[121] 
Muñoz-Jordan, J.L.; Sánchez-Burgos, G.G.; Laurent-Rolle, M.; García-Sastre, A. Inhibition of interferon signaling by dengue virus. Proc. Natl. Acad. Sci. USA,  2003, 100(24), 14333-14338.
[http://dx.doi.org/10.1073/pnas.2335168100] [PMID:  14612562] 
[122] 
Wu, R.H.; Tsai, M.H.; Tsai, K.N.; Tian, J.N.; Wu, J.S.; Wu, S.Y.; Chern, J.H.; Chen, C.H.; Yueh, A. Mutagenesis of dengue virus protein NS2A revealed a novel domain responsible for virus-induced cytopathic effect and interactions between NS2A and NS2B transmembrane segments. J. Virol.,  2017, 91(12), e01836-e16.
[http://dx.doi.org/10.1128/JVI.01836-16] [PMID:  28381578] 
[123] 
Wu, R.H.; Tsai, M.H.; Chao, D.Y.; Yueh, A. Scanning mutagenesis studies reveal a potential intramolecular interaction within the C-terminal half of dengue virus NS2A involved in viral RNA replication and virus assembly and secretion. J. Virol.,  2015, 89(8), 4281-4295.
[http://dx.doi.org/10.1128/JVI.03011-14] [PMID:  25653435] 
[124] 
Li, Y.; Lee, M.Y.; Loh, Y.R.; Kang, C. Secondary structure and membrane topology of dengue virus NS4A protein in micelles. Biochim. Biophys. Acta Biomembr.,  2018, 1860(2), 442-450.
[http://dx.doi.org/10.1016/j.bbamem.2017.10.016] [PMID:  29055659] 
[125] 
Miller, S.; Kastner, S.; Krijnse-Locker, J.; Bühler, S.; Bartenschlager, R. The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J. Biol. Chem.,  2007, 282(12), 8873-8882.
[http://dx.doi.org/10.1074/jbc.M609919200] [PMID:  17276984] 
[126] 
Teo, C.S.; Chu, J.J. Cellular vimentin regulates construction of dengue virus replication complexes through interaction with NS4A protein. J. Virol.,  2014, 88(4), 1897-1913.
[http://dx.doi.org/10.1128/JVI.01249-13] [PMID:  24284321] 
[127] 
Lee, C.M.; Xie, X.; Zou, J.; Li, S.H.; Lee, M.Y.; Dong, H.; Qin, C.F.; Kang, C.; Shi, P.Y. Determinants of dengue virus NS4A protein oligomerization. J. Virol.,  2015, 89(12), 6171-6183.
[http://dx.doi.org/10.1128/JVI.00546-15] [PMID:  25833044] 
[128] 
Stern, O.; Hung, Y.F.; Valdau, O.; Yaffe, Y.; Harris, E.; Hoffmann, S.; Willbold, D.; Sklan, E.H. An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication. J. Virol.,  2013, 87(7), 4080-4085.
[http://dx.doi.org/10.1128/JVI.01900-12] [PMID:  23325687] 
[129] 
McLean, J.E.; Wudzinska, A.; Datan, E.; Quaglino, D.; Zakeri, Z. Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. J. Biol. Chem.,  2011, 286(25), 22147-22159.
[http://dx.doi.org/10.1074/jbc.M110.192500] [PMID:  21511946] 
[130] 
Zou, J.; Xie, X.; Wang, Q.Y.; Dong, H.; Lee, M.Y.; Kang, C.; Yuan, Z.; Shi, P.Y. Characterization of dengue virus NS4A and NS4B protein interaction. J. Virol.,  2015, 89(7), 3455-3470.
[http://dx.doi.org/10.1128/JVI.03453-14] [PMID:  25568208] 
[131] 
Wang, P.; Li, L.F.; Wang, Q.Y.; Shang, L.Q.; Shi, P.Y.; Yin, Z. Anti-dengue-virus activity and structure-activity relationship studies of lycorine derivatives. Chem. Med. Chem,  2014, 9(7), 1522-1533.
[http://dx.doi.org/10.1002/cmdc.201300505] [PMID:  24574246] 
[132] 
Zmurko, J.; Neyts, J.; Dallmeier, K. Flaviviral NS4b, chameleon and jack-in-the-box roles in viral replication and pathogenesis, and a molecular target for antiviral intervention. Rev. Med. Virol.,  2015, 25(4), 205-223.
[http://dx.doi.org/10.1002/rmv.1835] [PMID:  25828437] 
[133] 
Xie, X.; Zou, J.; Wang, Q.Y.; Shi, P.Y. Targeting dengue virus NS4B protein for drug discovery. Antiviral Res.,  2015, 118, 39-45.
[http://dx.doi.org/10.1016/j.antiviral.2015.03.007] [PMID:  25796970] 
[134] 
Miller, S.; Sparacio, S.; Bartenschlager, R. Subcellular localization and membrane topology of the Dengue virus type 2 Non-structural protein 4B. J. Biol. Chem.,  2006, 281(13), 8854-8863.
[http://dx.doi.org/10.1074/jbc.M512697200] [PMID:  16436383] 
[135] 
Zou, J.; Xie, X.; Lee, T.; Chandrasekaran, R.; Reynaud, A.; Yap, L.; Wang, Q.Y.; Dong, H.; Kang, C.; Yuan, Z.; Lescar, J.; Shi, P.Y. Dimerization of flavivirus NS4B protein. J. Virol.,  2014, 88(6), 3379-3391.
[http://dx.doi.org/10.1128/JVI.02782-13] [PMID:  24390334] 
[136] 
Xie, X.; Wang, Q.Y.; Xu, H.Y.; Qing, M.; Kramer, L.; Yuan, Z.; Shi, P.Y. Inhibition of dengue virus by targeting viral NS4B protein. J. Virol.,  2011, 85(21), 11183-11195.
[http://dx.doi.org/10.1128/JVI.05468-11] [PMID:  21865382] 
[137] 
Umareddy, I.; Chao, A.; Sampath, A.; Gu, F.; Vasudevan, S.G. Dengue virus NS4B interacts with NS3 and dissociates it from single-stranded RNA. J. Gen. Virol.,  2006, 87(Pt 9), 2605-2614.
[http://dx.doi.org/10.1099/vir.0.81844-0] [PMID:  16894199] 
[138] 
van Cleef, K.W.; Overheul, G.J.; Thomassen, M.C.; Kaptein, S.J.; Davidson, A.D.; Jacobs, M.; Neyts, J.; van Kuppeveld, F.J.; van Rij, R.P. Identification of a new dengue virus inhibitor that targets the viral NS4B protein and restricts genomic RNA replication. Antiviral Res.,  2013, 99(2), 165-171.
[http://dx.doi.org/10.1016/j.antiviral.2013.05.011] [PMID:  23735301] 
[139] 
Wang, Q.Y.; Dong, H.; Zou, B.; Karuna, R.; Wan, K.F.; Zou, J.; Susila, A.; Yip, A.; Shan, C.; Yeo, K.L.; Xu, H.; Ding, M.; Chan, W.L.; Gu, F.; Seah, P.G.; Liu, W.; Lakshminarayana, S.B.; Kang, C.; Lescar, J.; Blasco, F.; Smith, P.W.; Shi, P.Y. Discovery of Dengue virus NS4B inhibitors. J. Virol.,  2015, 89(16), 8233-8244.
[http://dx.doi.org/10.1128/JVI.00855-15] [PMID:  26018165] 
[140] 
Bianchi, E.; Pessi, A. Inhibiting viral proteases: challenges and opportunities. Biopolymers,  2002, 66(2), 101-114.
[http://dx.doi.org/10.1002/bip.10230] [PMID:  12325160] 
[141] 
Arias, C.F.; Preugschat, F.; Strauss, J.H. Dengue 2 virus NS2B and NS3 form a stable complex that can cleave NS3 within the helicase domain. Virology,  1993, 193(2), 888-899.
[http://dx.doi.org/10.1006/viro.1993.1198] [PMID:  8460492] 
[142] 
Yusof, R.; Clum, S.; Wetzel, M.; Murthy, H.M.K.; Padmanabhan, R. Purified NS2B/NS3 serine protease of dengue virus type 2 exhibits cofactor NS2B dependence for cleavage of substrates with dibasic amino acids in vitro. J. Biol. Chem.,  2000, 275(14), 9963-9969.
[http://dx.doi.org/10.1074/jbc.275.14.9963] [PMID:  10744671] 
[143] 
Nestorowicz, A.; Chambers, T.J.; Rice, C.M. Mutagenesis of the yellow fever virus NS2A/2B cleavage site: effects on proteolytic processing, viral replication, and evidence for alternative processing of the NS2A protein. Virology,  1994, 199(1), 114-123.
[http://dx.doi.org/10.1006/viro.1994.1103] [PMID:  8116234] 
[144] 
Leung, D.; Schroder, K.; White, H.; Fang, N.X.; Stoermer, M.J.; Abbenante, G.; Martin, J.L.; Young, P.R.; Fairlie, D.P. Activity of recombinant dengue 2 virus NS3 protease in the presence of a truncated NS2B co-factor, small peptide substrates, and inhibitors. J. Biol. Chem.,  2001, 276(49), 45762-45771.
[http://dx.doi.org/10.1074/jbc.M107360200] [PMID:  11581268] 
[145] 
Chanprapaph, S.; Saparpakorn, P.; Sangma, C.; Niyomrattanakit, P.; Hannongbua, S.; Angsuthanasombat, C.; Katzenmeier, G. Competitive inhibition of the dengue virus NS3 serine protease by synthetic peptides representing polyprotein cleavage sites. Biochem. Biophys. Res. Commun.,  2005, 330(4), 1237-1246.
[http://dx.doi.org/10.1016/j.bbrc.2005.03.107] [PMID:  15823576] 
[146] 
Yin, Z.; Patel, S.J.; Wang, W.L.; Wang, G.; Chan, W.L.; Rao, K.R.R.; Alam, J.; Jeyaraj, D.A.; Ngew, X.; Patel, V.; Beer, D.; Lim, S.P.; Vasudevan, S.G.; Keller, T.H. Peptide inhibitors of dengue virus NS3 protease. Part 1: Warhead. Bioorg. Med. Chem. Lett.,  2006, 16(1), 36-39.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.062] [PMID:  16246553] 
[147] 
Yin, Z.; Patel, S.J.; Wang, W.L.; Chan, W.L.; Rao, R. K.R.; Wang, G.; Ngew, X.; Patel, V.; Beer, D.; Knox, J.E.; Ma, N.L.; Ehrhardt, C.; Lim, S.P.; Vasudevan, S.G.; Keller, T.H. Peptide inhibitors of dengue virus NS3 protease. Part 2: SAR study of tetrapeptide aldehyde inhibitors. Bioorg. Med. Chem. Lett.,  2006, 16(1), 40-43.
[http://dx.doi.org/10.1016/j.bmcl.2005.09.049] [PMID:  16246563] 
[148] 
Noble, C.G.; Seh, C.C.; Chao, A.T.; Shi, P.Y. Ligand-bound structures of the dengue virus protease reveal the active conformation. J. Virol.,  2012, 86(1), 438-446.
[http://dx.doi.org/10.1128/JVI.06225-11] [PMID:  22031935] 
[149] 
Schüller, A.; Yin, Z.; Brian Chia, C.S.; Doan, D.N.P.; Kim, H.K.; Shang, L.; Loh, T.P.; Hill, J.; Vasudevan, S.G. Tripeptide inhibitors of dengue and West Nile virus NS2B-NS3 protease. Antiviral Res.,  2011, 92(1), 96-101.
[http://dx.doi.org/10.1016/j.antiviral.2011.07.002] [PMID:  21763725] 
[150] 
Nitsche, C.; Behnam, M.A.M.; Steuer, C.; Klein, C.D. Retro peptide-hybrids as selective inhibitors of the Dengue virus NS2B-NS3 protease. Antiviral Res.,  2012, 94(1), 72-79.
[http://dx.doi.org/10.1016/j.antiviral.2012.02.008] [PMID:  22391061] 
[151] 
Nitsche, C.; Schreier, V.N.; Behnam, M.A.M.; Kumar, A.; Bartenschlager, R.; Klein, C.D. Thiazolidinone-peptide hybrids as Dengue virus protease inhibitors with antiviral activity in cell culture. J. Med. Chem.,  2013, 56(21), 8389-8403.
[http://dx.doi.org/10.1021/jm400828u] [PMID:  24083834] 
[152] 
Behnam, M.A.M.; Nitsche, C.; Vechi, S.M.; Klein, C.D. C-terminal residue optimization and fragment merging: discovery of a potent Peptide-hybrid inhibitor of dengue protease. ACS Med. Chem. Lett.,  2014, 5(9), 1037-1042.
[http://dx.doi.org/10.1021/ml500245v] [PMID:  25221663] 
[153] 
Bastos Lima, A.; Behnam, M.A.M.; El Sherif, Y.; Nitsche, C.; Vechi, S.M.; Klein, C.D. Dual inhibitors of the Dengue and West Nile virus NS2B-NS3 proteases: synthesis, biological evaluation and docking studies of novel peptide-hybrids. Bioorg. Med. Chem.,  2015, 23(17), 5748-5755.
[http://dx.doi.org/10.1016/j.bmc.2015.07.012] [PMID:  26233795] 
[154] 
Behnam, M.A.M.; Graf, D.; Bartenschlager, R.; Zlotos, D.P.; Klein, C.D. Discovery of nanomolar Dengue and West Nile virus protease inhibitors containing a 4-benzyloxyphenylglycine residue. J. Med. Chem.,  2015, 58(23), 9354-9370.
[http://dx.doi.org/10.1021/acs.jmedchem.5b01441] [PMID:  26562070] 
[155] 
Weigel, L.F.; Nitsche, C.; Graf, D.; Bartenschlager, R.; Klein, C.D. Phenylalanine and Phenylglycine Analogues as Arginine Mimetics in Dengue Protease Inhibitors. J. Med. Chem.,  2015, 58(19), 7719-7733.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00612] [PMID:  26367391] 
[156] 
Nitsche, C.; Zhang, L.; Weigel, L.F.; Schilz, J.; Graf, D.; Bartenschlager, R.; Hilgenfeld, R.; Klein, C.D. Peptide-boronic acid inhibitors of flaviviral proteases: medicinal chemistry and structural biology. J. Med. Chem.,  2017, 60(1), 511-516.
[http://dx.doi.org/10.1021/acs.jmedchem.6b01021] [PMID:  27966962] 
[157] 
Zhou, G.C.; Weng, Z.; Shao, X.; Liu, F.; Nie, X.; Liu, J.; Wang, D.; Wang, C.; Guo, K. Discovery and SAR studies of methionine-proline anilides as Dengue virus NS2B-NS3 protease inhibitors. Bioorg. Med. Chem. Lett.,  2013, 23(24), 6549-6554.
[http://dx.doi.org/10.1016/j.bmcl.2013.10.071] [PMID:  24268549] 
[158] 
Weng, Z.; Shao, X.; Graf, D.; Wang, C.; Klein, C.D.; Wang, J.; Zhou, G.C. Identification of fused bicyclic derivatives of pyrrolidine and imidazolidinone as dengue virus-2 NS2B-NS3 protease inhibitors. Eur. J. Med. Chem.,  2017, 125, 751-759.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.063] [PMID:  27721158] 
[159] 
Prusis, P.; Lapins, M.; Yahorava, S.; Petrovska, R.; Niyomrattanakit, P.; Katzenmeier, G.; Wikberg, J.E.S. Proteochemometrics analysis of substrate interactions with dengue virus NS3 proteases. Bioorg. Med. Chem.,  2008, 16(20), 9369-9377.
[http://dx.doi.org/10.1016/j.bmc.2008.08.081] [PMID:  18824362] 
[160] 
Prusis, P.; Junaid, M.; Petrovska, R.; Yahorava, S.; Yahorau, A.; Katzenmeier, G.; Lapins, M.; Wikberg, J.E. Design and evaluation of substrate-based octapeptide and non substrate-based tetrapeptide inhibitors of dengue virus NS2B-NS3 proteases. Biochem. Biophys. Res. Commun.,  2013, 434(4), 767-772.
[http://dx.doi.org/10.1016/j.bbrc.2013.03.139] [PMID:  23587903] 
[161] 
Rothan, H.A.; Bahrani, H.; Rahman, N.A.; Yusof, R. Identification of natural antimicrobial agents to treat dengue infection: in vitro analysis of latarcin peptide activity against dengue virus. BMC Microbiol.,  2014, 14, 140.
[http://dx.doi.org/10.1186/1471-2180-14-140] [PMID:  24885331] 
[162] 
Cui, T.A.; Puah, C.M.; Liew, O.W.; Lee, S.H. Novel polypeptides for anti-viral treatment, 2007.
[163] 
Gao, Y.; Cui, T.; Lam, Y. Synthesis and disulfide bond connectivity-activity studies of a kalata B1-inspired cyclopeptide against dengue NS2B-NS3 protease. Bioorg. Med. Chem.,  2010, 18(3), 1331-1336.
[http://dx.doi.org/10.1016/j.bmc.2009.12.026] [PMID:  20042339] 
[164] 
Xu, S.; Li, H.; Shao, X.; Fan, C.; Ericksen, B.; Liu, J.; Chi, C.; Wang, C. Critical effect of peptide cyclization on the potency of peptide inhibitors against Dengue virus NS2B-NS3 protease. J. Med. Chem.,  2012, 55(15), 6881-6887.
[http://dx.doi.org/10.1021/jm300655h] [PMID:  22780881] 
[165] 
Rothan, H.A.; Han, H.C.; Ramasamy, T.S.; Othman, S.; Rahman, N.A.; Yusof, R. Inhibition of dengue NS2B-NS3 protease and viral replication in vero cells by recombinant retrocyclin-1. BMC Infect. Dis.,  2012, 12, 314.
[http://dx.doi.org/10.1186/1471-2334-12-314] [PMID:  23171075] 
[166] 
Rothan, H.A.; Abdulrahman, A.Y.; Sasikumer, P.G.; Othman, S.; Rahman, N.A.; Yusof, R. Protegrin-1 inhibits dengue NS2B-NS3 serine protease and viral replication in MK2 cells. J. Biomed. Biotechnol., 2012., 2012251482
[http://dx.doi.org/10.1155/2012/251482] [PMID:  23093838] 
[167] 
Rothan, H.A.; Mohamed, Z.; Suhaeb, A.M.; Rahman, N.A.; Yusof, R. Antiviral cationic peptides as a strategy for innovation in global health therapeutics for Dengue virus: high yield production of the biologically active recombinant plectasin peptide. OMICS,  2013, 17(11), 560-567.
[http://dx.doi.org/10.1089/omi.2013.0056] [PMID:  24044366] 
[168] 
Rothan, H.A.; Bahrani, H.; Mohamed, Z.; Abd Rahman, N.; Yusof, R. Fusion of protegrin-1 and plectasin to MAP30 shows significant inhibition activity against dengue virus replication. PLoS One,  2014, 9(4), e94561.
[http://dx.doi.org/10.1371/journal.pone.0094561] [PMID:  24722532] 
[169] 
Lin, K.H.; Ali, A.; Rusere, L.; Soumana, D.I.; Kurt Yilmaz, N.; Schiffer, C.A. Dengue virus NS2B/NS3 protease inhibitors exploiting the prime side. J. Virol.,  2017, 91(10), e00045-e17.
[http://dx.doi.org/10.1128/JVI.00045-17] [PMID:  28298600] 
[170] 
Takagi, Y.; Matsui, K.; Nobori, H.; Maeda, H.; Sato, A.; Kurosu, T.; Orba, Y.; Sawa, H.; Hattori, K.; Higashino, K.; Numata, Y.; Yoshida, Y. Discovery of novel cyclic peptide inhibitors of dengue virus NS2B-NS3 protease with antiviral activity. Bioorg. Med. Chem. Lett.,  2017, 27(15), 3586-3590.
[http://dx.doi.org/10.1016/j.bmcl.2017.05.027] [PMID:  28539222] 
[171] 
Bhakat, S.; Delang, L.; Kaptein, S.; Neyts, J.; Leyssen, P.; Jayaprakash, V. Reaching beyond HIV/HCV: nelfinavir as a potential starting point for broad-spectrum protease inhibitors against Dengue and Chikungunya virus. Rsc Adv,  2015, 5(104), 85938-85949.
[http://dx.doi.org/10.1039/C5RA14469H] 
[172] 
Kouretova, J.; Hammamy, M.Z.; Epp, A.; Hardes, K.; Kallis, S.; Zhang, L.; Hilgenfeld, R.; Bartenschlager, R.; Steinmetzer, T. Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 712-721.
[http://dx.doi.org/10.1080/14756366.2017.1306521] [PMID:  28385094] 
[173] 
Kiat, T.S.; Pippen, R.; Yusof, R.; Ibrahim, H.; Khalid, N.; Rahman, N.A. Inhibitory activity of cyclohexenyl chalcone derivatives and flavonoids of fingerroot, Boesenbergia rotunda (L.), towards dengue-2 virus NS3 protease. Bioorg. Med. Chem. Lett.,  2006, 16(12), 3337-3340.
[http://dx.doi.org/10.1016/j.bmcl.2005.12.075] [PMID:  16621533] 
[174] 
Othman, R.; Kiat, T.S.; Khalid, N.; Yusof, R.; Newhouse, E.I.; Newhouse, J.S.; Alam, M.; Rahman, N.A. Docking of noncompetitive inhibitors into Dengue virus type 2 protease: understanding the interactions with allosteric binding sites. J. Chem. Inf. Model.,  2008, 48(8), 1582-1591.
[http://dx.doi.org/10.1021/ci700388k] [PMID:  18656912] 
[175] 
Heh, C.H.; Othman, R.; Buckle, M.J.C.; Sharifuddin, Y.; Yusof, R.; Rahman, N.A. Rational discovery of dengue type 2 non-competitive inhibitors. Chem. Biol. Drug Des.,  2013, 82(1), 1-11.
[http://dx.doi.org/10.1111/cbdd.12122] [PMID:  23421589] 
[176] 
de Sousa, L.R.F.; Wu, H.; Nebo, L.; Fernandes, J.B.; da Silva, M.F.D.F.; Kiefer, W.; Kanitz, M.; Bodem, J.; Diederich, W.E.; Schirmeister, T.; Vieira, P.C. Flavonoids as noncompetitive inhibitors of Dengue virus NS2B-NS3 protease: inhibition kinetics and docking studies. Bioorg. Med. Chem.,  2015, 23(3), 466-470.
[http://dx.doi.org/10.1016/j.bmc.2014.12.015] [PMID:  25564380] 
[177] 
Shen, X.; Chen, J.; Lee, J.; Mao, F. use of procyanidin in preparation of drugs for treatment of diseases caused by dengue virus infection, china. patent cn105748462a, 2016.
[178] 
Osman, H.; Idris, N.H.; Kamarulzaman, E.E.; Wahab, H.A.; Hassan, M.Z. 3,5-Bis(arylidene)-4-piperidones as potential dengue protease inhibitors. Acta Pharm. Sin. B,  2017, 7(4), 479-484.
[http://dx.doi.org/10.1016/j.apsb.2017.04.009] [PMID:  28752033] 
[179] 
Cregar-Hernandez, L.; Jiao, G-S.; Johnson, A.T.; Lehrer, A.T.; Wong, T.A.S.; Margosiak, S.A. Small molecule pan-dengue and West Nile virus NS3 protease inhibitors. Antivir. Chem. Chemother.,  2011, 21(5), 209-217.
[http://dx.doi.org/10.3851/IMP1767] [PMID:  21566267] 
[180] 
Nitsche, C.; Steuer, C.; Klein, C.D. Arylcyanoacrylamides as inhibitors of the Dengue and West Nile virus proteases. Bioorg. Med. Chem.,  2011, 19(24), 7318-7337.
[http://dx.doi.org/10.1016/j.bmc.2011.10.061] [PMID:  22094280] 
[181] 
Aravapalli, S.; Lai, H.; Teramoto, T.; Alliston, K.R.; Lushington, G.H.; Ferguson, E.L.; Padmanabhan, R.; Groutas, W.C. Inhibitors of Dengue virus and West Nile virus proteases based on the aminobenzamide scaffold. Bioorg. Med. Chem.,  2012, 20(13), 4140-4148.
[http://dx.doi.org/10.1016/j.bmc.2012.04.055] [PMID:  22632792] 
[182] 
Tiew, K.C.; Dou, D.; Teramoto, T.; Lai, H.; Alliston, K.R.; Lushington, G.H.; Padmanabhan, R.; Groutas, W.C. Inhibition of Dengue virus and West Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives. Bioorg. Med. Chem.,  2012, 20(3), 1213-1221.
[http://dx.doi.org/10.1016/j.bmc.2011.12.047] [PMID:  22249124] 
[183] 
Irwin, J.J.; Shoichet, B.K. ZINC--a free database of commercially available compounds for virtual screening. J. Chem. Inf. Model.,  2005, 45(1), 177-182.
[http://dx.doi.org/10.1021/ci049714+] [PMID:  15667143] 
[184] 
Lai, H.; Sridhar Prasad, G.; Padmanabhan, R. Characterization of 8-hydroxyquinoline derivatives containing aminobenzothiazole as inhibitors of dengue virus type 2 protease in vitro. Antiviral Res.,  2013, 97(1), 74-80.
[http://dx.doi.org/10.1016/j.antiviral.2012.10.009] [PMID:  23127365] 
[185] 
Lai, H.; Dou, D.; Aravapalli, S.; Teramoto, T.; Lushington, G.H.; Mwania, T.M.; Alliston, K.R.; Eichhorn, D.M.; Padmanabhan, R.; Groutas, W.C. Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. Bioorg. Med. Chem.,  2013, 21(1), 102-113.
[http://dx.doi.org/10.1016/j.bmc.2012.10.058] [PMID:  23211969] 
[186] 
Liu, H.; Wu, R.; Sun, Y.; Ye, Y.; Chen, J.; Luo, X.; Shen, X.; Liu, H. Identification of novel thiadiazoloacrylamide analogues as inhibitors of dengue-2 virus NS2B/NS3 protease. Bioorg. Med. Chem.,  2014, 22(22), 6344-6352.
[http://dx.doi.org/10.1016/j.bmc.2014.09.057] [PMID:  25438757] 
[187] 
Padmanabhan, R.; Nagarajan, K.; Rao, K. S.; Shridhara, K. shashiprabha; harisha, a. s., dengue and west nile virus protease inhibitors. pct int. appl., 2014, wo 2014164667 a1 20141009. 
[188] 
Timiri, A.K.; Selvarasu, S.; Kesherwani, M.; Vijayan, V.; Sinha, B.N.; Devadasan, V.; Jayaprakash, V. Synthesis and molecular modelling studies of novel sulphonamide derivatives as dengue virus 2 protease inhibitors. Bioorg. Chem.,  2015, 62, 74-82.
[http://dx.doi.org/10.1016/j.bioorg.2015.07.005] [PMID:  26247308] 
[189] 
Wu, H.; Bock, S.; Snitko, M.; Berger, T.; Weidner, T.; Holloway, S.; Kanitz, M.; Diederich, W.E.; Steuber, H.; Walter, C.; Hofmann, D.; Weißbrich, B.; Spannaus, R.; Acosta, E.G.; Bartenschlager, R.; Engels, B.; Schirmeister, T.; Bodem, J. Novel dengue virus NS2B/NS3 protease inhibitors. Antimicrob. Agents Chemother.,  2015, 59(2), 1100-1109.
[http://dx.doi.org/10.1128/AAC.03543-14] [PMID:  25487800] 
[190] 
Pelliccia, S.; Wu, Y.H.; Coluccia, A.; La Regina, G.; Tseng, C.K.; Famiglini, V.; Masci, D.; Hiscott, J.; Lee, J.C.; Silvestri, R. Inhibition of Dengue virus replication by novel inhibitors of RNA-dependent RNA polymerase and protease activities. J. Enzyme Inhib. Med. Chem.,  2017, 32(1), 1091-1101.
[http://dx.doi.org/10.1080/14756366.2017.1355791] [PMID:  28776445] 
[191] 
Rothan, H.A.; Buckle, M.J.; Ammar, Y.A.; Mohammadjavad, P.; Shatrah, O.; Noorsaadah, A.R.; Rohana, Y. Study the antiviral activity of some derivatives of tetracycline and non-steroid anti-inflammatory drugs towards Dengue virus. Trop. Biomed.,  2013, 30(4), 681-690.
[PMID:  24522138] 
[192] 
Wu, D.W.; Mao, F.; Ye, Y.; Li, J.; Xu, C.L.; Luo, X.M.; Chen, J.; Shen, X. Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells. Acta Pharmacol. Sin.,  2015, 36(9), 1126-1136.
[http://dx.doi.org/10.1038/aps.2015.56] [PMID:  26279156] 
[193] 
Li, Z.; Sakamuru, S.; Huang, R.; Brecher, M.; Koetzner, C.A.; Zhang, J.; Chen, H.; Qin, C.F.; Zhang, Q.-Y.; Zhou, J.; Kramer, L.D.; Xia, M.; Li, H. Erythrosin B is a potent and broad-spectrum orthosteric inhibitor of the flavivirus NS2B-NS3 protease. Antiviral Res.,  2018, 150, 217-225.
[http://dx.doi.org/10.1016/j.antiviral.2017.12.018] [PMID:  29288700] 
[194] 
Yang, C.C.; Hsieh, Y.C.; Lee, S.J.; Wu, S.H.; Liao, C.L.; Tsao, C.H.; Chao, Y.S.; Chern, J.H.; Wu, C.P.; Yueh, A. Novel dengue virus-specific NS2B/NS3 protease inhibitor, BP2109, discovered by a high-throughput screening assay. Antimicrob. Agents Chemother.,  2011, 55(1), 229-238.
[http://dx.doi.org/10.1128/AAC.00855-10] [PMID:  20937790] 
[195] 
Balasubramanian, A.; Manzano, M.; Teramoto, T.; Pilankatta, R.; Padmanabhan, R. High-throughput screening for the identification of small-molecule inhibitors of the flaviviral protease. Antiviral Res.,  2016, 134, 6-16.
[http://dx.doi.org/10.1016/j.antiviral.2016.08.014] [PMID:  27539384] 
[196] 
Tomlinson, S.M.; Malmstrom, R.D.; Russo, A.; Mueller, N.; Pang, Y-P.; Watowich, S.J. Structure-based discovery of dengue virus protease inhibitors. Antiviral Res.,  2009, 82(3), 110-114.
[http://dx.doi.org/10.1016/j.antiviral.2009.02.190] [PMID:  19428601] 
[197] 
Tomlinson, S.M.; Watowich, S.J. Anthracene-based inhibitors of dengue virus NS2B-NS3 protease. Antiviral Res.,  2011, 89(2), 127-135.
[http://dx.doi.org/10.1016/j.antiviral.2010.12.006] [PMID:  21185332] 
[198] 
Watowich, S.J.; Tomlinson, S.M.; Gilbertson, S. smallmolecule inhibitors of dengue and west nile virus proteases. u.s. pat. appl. publ., us 20130035284 a1 20130207, 2013.
[199] 
Watowich, S.J.; Viswanathan, U. small-molecule inhibitors of dengue virus proteases. u.s. pat. appl. publ., us 20150141521 a1 20150521, 2015.
[200] 
Viswanathan, U.; Tomlinson, S.M.; Fonner, J.M.; Mock, S.A.; Watowich, S.J. Identification of a novel inhibitor of dengue virus protease through use of a virtual screening drug discovery Web portal. J. Chem. Inf. Model.,  2014, 54(10), 2816-2825.
[http://dx.doi.org/10.1021/ci500531r] [PMID:  25263519] 
[201] 
Tomlinson, S.M.; Watowich, S.J. Use of parallel validation high-throughput screens to reduce false positives and identify novel dengue NS2B-NS3 protease inhibitors. Antiviral Res.,  2012, 93(2), 245-252.
[http://dx.doi.org/10.1016/j.antiviral.2011.12.003] [PMID:  22193283] 
[202] 
Deng, J.; Li, N.; Liu, H.; Zuo, Z.; Liew, O.W.; Xu, W.; Chen, G.; Tong, X.; Tang, W.; Zhu, J.; Zuo, J.; Jiang, H.; Yang, C.G.; Li, J.; Zhu, W. Discovery of novel small molecule inhibitors of dengue viral NS2B-NS3 protease using virtual screening and scaffold hopping. J. Med. Chem.,  2012, 55(14), 6278-6293.
[http://dx.doi.org/10.1021/jm300146f] [PMID:  22742496] 
[203] 
Pambudi, S.; Kawashita, N.; Phanthanawiboon, S.; Omokoko, M.D.; Masrinoul, P.; Yamashita, A.; Limkittikul, K.; Yasunaga, T.; Takagi, T.; Ikuta, K.; Kurosu, T. A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication. Biochem. Biophys. Res. Commun.,  2013, 440(3), 393-398.
[http://dx.doi.org/10.1016/j.bbrc.2013.09.078] [PMID:  24070610] 
[204] 
Nguyen, T.T.H.; Lee, S.; Wang, H.K.; Chen, H.Y.; Wu, Y.T.; Lin, S.C.; Kim, D.W.; Kim, D. In vitro evaluation of novel inhibitors against the NS2B-NS3 protease of dengue fever virus type 4. Molecules,  2013, 18(12), 15600-15612.
[http://dx.doi.org/10.3390/molecules181215600] [PMID:  24352016] 
[205] 
Mukhametov, A.; Newhouse, E.I.; Aziz, N.A.; Saito, J.A.; Alam, M. Allosteric pocket of the dengue virus (serotype 2) NS2B/NS3 protease: in silico ligand screening and molecular dynamics studies of inhibition. J. Mol. Graph. Model.,  2014, 52, 103-113.
[http://dx.doi.org/10.1016/j.jmgm.2014.06.008] [PMID:  25023665] 
[206] 
Raut, R.; Beesetti, H.; Tyagi, P.; Khanna, I.; Jain, S.K.; Jeankumar, V.U.; Yogeeswari, P.; Sriram, D.; Swaminathan, S. A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture. Virol. J.,  2015, 12, 16.
[http://dx.doi.org/10.1186/s12985-015-0248-x] [PMID:  25886260] 
[207] 
Cabarcas-Montalvo, M.; Maldonado-Rojas, W.; Montes-Grajales, D.; Bertel-Sevilla, A.; Wagner-Döbler, I.; Sztajer, H.; Reck, M.; Flechas-Alarcon, M.; Ocazionez, R.; Olivero-Verbel, J. Discovery of antiviral molecules for dengue: in silico search and biological evaluation. Eur. J. Med. Chem.,  2016, 110, 87-97.
[http://dx.doi.org/10.1016/j.ejmech.2015.12.030] [PMID:  26807547] 
[208] 
Brecher, M.; Li, Z.; Liu, B.; Zhang, J.; Koetzner, C.A.; Alifarag, A.; Jones, S.A.; Lin, Q.; Kramer, L.D.; Li, H. A conformational switch high-throughput screening assay and allosteric inhibition of the flavivirus NS2B-NS3 protease. PLoS Pathog.,  2017, 13(5), e1006411.
[http://dx.doi.org/10.1371/journal.ppat.1006411] [PMID:  28542603] 
[209] 
Mirza, S.B.; Lee, R.C.H.; Chu, J.J.H.; Salmas, R.E.; Mavromoustakos, T.; Durdagi, S. Discovery of selective dengue virus inhibitors using combination of molecular fingerprint-based virtual screening protocols, structure-based pharmacophore model development, molecular dynamics simulations and in vitro studies. J. Mol. Graph. Model.,  2017, 77, 338-355.
[PMID:  28957754] 
[210] 
Knehans, T.; Schüller, A.; Doan, D.N.; Nacro, K.; Hill, J.; Güntert, P.; Madhusudhan, M.S.; Weil, T.; Vasudevan, S.G. Structure-guided fragment-based in silico drug design of dengue protease inhibitors. J. Comput. Aided Mol. Des.,  2011, 25(3), 263-274.
[http://dx.doi.org/10.1007/s10822-011-9418-0] [PMID:  21344277] 
[211] 
Steuer, C.; Gege, C.; Fischl, W.; Heinonen, K.H.; Bartenschlager, R.; Klein, C.D. Synthesis and biological evaluation of α-ketoamides as inhibitors of the Dengue virus protease with antiviral activity in cell-culture. Bioorg. Med. Chem.,  2011, 19(13), 4067-4074.
[http://dx.doi.org/10.1016/j.bmc.2011.05.015] [PMID:  21641807] 
[212] 
Li, L.; Basavannacharya, C.; Chan, K.W.K.; Shang, L.; Vasudevan, S.G.; Yin, Z. Structure-guided discovery of a novel non-peptide inhibitor of Dengue virus NS2B-NS3 protease. Chem. Biol. Drug Des.,  2015, 86(3), 255-264.
[http://dx.doi.org/10.1111/cbdd.12500] [PMID:  25533891] 
[213] 
Chiang, P.Y.; Wu, H.N. The role of surface basic amino acids of dengue virus NS3 helicase in viral RNA replication and enzyme activities. FEBS Lett.,  2016, 590(14), 2307-2320.
[http://dx.doi.org/10.1002/1873-3468.12232] [PMID:  27273003] 
[214] 
Luo, D.; Xu, T.; Hunke, C.; Grüber, G.; Vasudevan, S.G.; Lescar, J. Crystal structure of the NS3 protease-helicase from Dengue virus. J. Virol.,  2008, 82(1), 173-183.
[http://dx.doi.org/10.1128/JVI.01788-07] [PMID:  17942558] 
[215] 
Sampath, A.; Xu, T.; Chao, A.; Luo, D.; Lescar, J.; Vasudevan, S.G. Structure-based mutational analysis of the NS3 helicase from Dengue virus. J. Virol.,  2006, 80(13), 6686-6690.
[http://dx.doi.org/10.1128/JVI.02215-05] [PMID:  16775356] 
[216] 
Swarbrick, C.M.D.; Basavannacharya, C.; Chan, K.W.K.; Chan, S.A.; Singh, D.; Wei, N.; Phoo, W.W.; Luo, D.; Lescar, J.; Vasudevan, S.G. NS3 helicase from Dengue virus specifically recognizes viral RNA sequence to ensure optimal replication. Nucleic Acids Res.,  2017, 45(22), 12904-12920.
[http://dx.doi.org/10.1093/nar/gkx1127] [PMID:  29165589] 
[217] 
Luo, D.; Xu, T.; Watson, R.P.; Scherer-Becker, D.; Sampath, A.; Jahnke, W.; Yeong, S.S.; Wang, C.H.; Lim, S.P.; Strongin, A.; Vasudevan, S.G.; Lescar, J. Insights into RNA unwinding and ATP hydrolysis by the flavivirus NS3 protein. EMBO J.,  2008, 27(23), 3209-3219.
[http://dx.doi.org/10.1038/emboj.2008.232] [PMID:  19008861] 
[218] 
Borowski, P.; Niebuhr, A.; Schmitz, H.; Hosmane, R.S.; Bretner, M.; Siwecka, M.A.; Kulikowski, T. NTPase/helicase of Flaviviridae: inhibitors and inhibition of the enzyme. Acta Biochim. Pol.,  2002, 49(3), 597-614.
[http://dx.doi.org/10.18388/abp.2002_3769] [PMID:  12422230] 
[219] 
da Costa, E.C.; Amorim, R.; da Silva, F.C.; Rocha, D.R.; Papa, M.P.; de Arruda, L.B.; Mohana-Borges, R.; Ferreira, V.F.; Tanuri, A.; da Costa, L.J.; Ferreira, S.B. Synthetic 1,4-pyran naphthoquinones are potent inhibitors of Dengue virus replication. PLoS One,  2013, 8(12), e82504.
[http://dx.doi.org/10.1371/journal.pone.0082504] [PMID:  24376541] 
[220] 
Sweeney, N.L.; Hanson, A.M.; Mukherjee, S.; Ndjomou, J.; Geiss, B.J.; Steel, J.J.; Frankowski, K.J.; Li, K.; Schoenen, F.J.; Frick, D.N. Benzothiazole and pyrrolone Flavivirus inhibitors targeting the viral helicase. ACS Infect. Dis.,  2015, 1(3), 140-148.
[http://dx.doi.org/10.1021/id5000458] [PMID:  26029739] 
[221] 
Pan, A.; Saw, W.G.; Subramanian Manimekalai, M.S.; Grüber, A.; Joon, S.; Matsui, T.; Weiss, T.M.; Grüber, G. Structural features of NS3 of Dengue virus serotypes 2 and 4 in solution and insight into RNA binding and the inhibitory role of quercetin. Acta Crystallogr. D Struct. Biol.,  2017, 73(Pt 5), 402-419.
[http://dx.doi.org/10.1107/S2059798317003849] [PMID:  28471365] 
[222] 
Byrd, C.M.; Grosenbach, D.W.; Berhanu, A.; Dai, D.; Jones, K.F.; Cardwell, K.B.; Schneider, C.; Yang, G.; Tyavanagimatt, S.; Harver, C.; Wineinger, K.A.; Page, J.; Stavale, E.; Stone, M.A.; Fuller, K.P.; Lovejoy, C.; Leeds, J.M.; Hruby, D.E.; Jordan, R. Novel benzoxazole inhibitor of dengue virus replication that targets the NS3 helicase. Antimicrob. Agents Chemother.,  2013, 57(4), 1902-1912.
[http://dx.doi.org/10.1128/AAC.02251-12] [PMID:  23403421] 
[223] 
Basavannacharya, C.; Vasudevan, S.G. Suramin inhibits helicase activity of NS3 protein of Dengue virus in a fluorescence-based high throughput assay format. Biochem. Biophys. Res. Commun.,  2014, 453(3), 539-544.
[http://dx.doi.org/10.1016/j.bbrc.2014.09.113] [PMID:  25281902] 
[224] 
Mastrangelo, E.; Pezzullo, M.; De Burghgraeve, T.; Kaptein, S.; Pastorino, B.; Dallmeier, K.; de Lamballerie, X.; Neyts, J.; Hanson, A.M.; Frick, D.N.; Bolognesi, M.; Milani, M. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J. Antimicrob. Chemother.,  2012, 67(8), 1884-1894.
[http://dx.doi.org/10.1093/jac/dks147] [PMID:  22535622] 
[225] 
El Sahili, A.; Lescar, J. Dengue virus non-structural protein 5. Viruses,  2017, 9(4), E91.
[http://dx.doi.org/10.3390/v9040091] [PMID:  28441781] 
[226] 
Potisopon, S.; Priet, S.; Collet, A.; Decroly, E.; Canard, B.; Selisko, B. The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain. Nucleic Acids Res.,  2016, 44(6), 2974.
[http://dx.doi.org/10.1093/nar/gkv1294] [PMID:  26578566] 
[227] 
Klema, V.J.; Ye, M.; Hindupur, A.; Teramoto, T.; Gottipati, K.; Padmanabhan, R.; Choi, K.H. Dengue Virus Nonstructural Protein 5 (NS5) Assembles into a Dimer with a Unique Methyltransferase and Polymerase Interface. PLoS Pathog.,  2016, 12(2)e1005451
[http://dx.doi.org/10.1371/journal.ppat.1005451] [PMID:  26895240] 
[228] 
Dong, H.; Fink, K.; Züst, R.; Lim, S.P.; Qin, C.F.; Shi, P.Y. Flavivirus RNA methylation. J. Gen. Virol.,  2014, 95(Pt 4), 763-778.
[http://dx.doi.org/10.1099/vir.0.062208-0] [PMID:  24486628] 
[229] 
Zhou, Y.; Ray, D.; Zhao, Y.; Dong, H.; Ren, S.; Li, Z.; Guo, Y.; Bernard, K.A.; Shi, P.Y.; Li, H. Structure and function of flavivirus NS5 methyltransferase. J. Virol.,  2007, 81(8), 3891-3903.
[http://dx.doi.org/10.1128/JVI.02704-06] [PMID:  17267492] 
[230] 
Dong, H.; Liu, L.; Zou, G.; Zhao, Y.; Li, Z.; Lim, S.P.; Shi, P.Y.; Li, H. Structural and functional analyses of a conserved hydrophobic pocket of flavivirus methyltransferase. J. Biol. Chem.,  2010, 285(42), 32586-32595.
[http://dx.doi.org/10.1074/jbc.M110.129197] [PMID:  20685660] 
[231] 
Lim, S.P.; Sonntag, L.S.; Noble, C.; Nilar, S.H.; Ng, R.H.; Zou, G.; Monaghan, P.; Chung, K.Y.; Dong, H.; Liu, B.; Bodenreider, C.; Lee, G.; Ding, M.; Chan, W.L.; Wang, G.; Jian, Y.L.; Chao, A.T.; Lescar, J.; Yin, Z.; Vedananda, T.R.; Keller, T.H.; Shi, P.Y. Small molecule inhibitors that selectively block dengue virus methyltransferase. J. Biol. Chem.,  2011, 286(8), 6233-6240.
[http://dx.doi.org/10.1074/jbc.M110.179184] [PMID:  21147775] 
[232] 
Egloff, M.P.; Decroly, E.; Malet, H.; Selisko, B.; Benarroch, D.; Ferron, F.; Canard, B. Structural and functional analysis of methylation and 5′-RNA sequence requirements of short capped RNAs by the methyltransferase domain of dengue virus NS5. J. Mol. Biol.,  2007, 372(3), 723-736.
[http://dx.doi.org/10.1016/j.jmb.2007.07.005] [PMID:  17686489] 
[233] 
Henderson, B.R.; Saeedi, B.J.; Campagnola, G.; Geiss, B.J. Analysis of RNA binding by the dengue virus NS5 RNA capping enzyme. PLoS One,  2011, 6(10), e25795.
[http://dx.doi.org/10.1371/journal.pone.0025795] [PMID:  22022449] 
[234] 
Chung, K.Y.; Dong, H.; Chao, A.T.; Shi, P.Y.; Lescar, J.; Lim, S.P. Higher catalytic efficiency of N-7-methylation is responsible for processive N-7 and 2′-O methyltransferase activity in dengue virus. Virology,  2010, 402(1), 52-60.
[http://dx.doi.org/10.1016/j.virol.2010.03.011] [PMID:  20350738] 
[235] 
Noble, C.G.; Li, S.H.; Dong, H.; Chew, S.H.; Shi, P.Y. Crystal structure of Dengue virus methyltransferase without S-adenosyl-L-methionine. Antiviral Res.,  2014, 111, 78-81.
[http://dx.doi.org/10.1016/j.antiviral.2014.09.003] [PMID:  25241250] 
[236] 
Zweygarth, E.; Schillinger, D.; Kaufmann, W.; Rottcher, D.  evaluation of sinefungin for the treatment of trypanosoma (nannomonas) congolense infections in goats. tropical medicine and parasitology : official organ of deutsche tropenmedizinische gesellschaft and of deutsche gesellschaft fur technische zusammenarbeit, 1986, 37(3), 255-257.
[237] 
Trott, O.; Olson, A.J. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J. Comput. Chem.,  2010, 31(2), 455-461.
[http://dx.doi.org/10.1002/jcc.21334]] [PMID:  19499576] 
[238] 
Brecher, M.; Chen, H.; Li, Z.; Banavali, N.K.; Jones, S.A.; Zhang, J.; Kramer, L.D.; Li, H. Identification and characterization of novel broad-spectrum inhibitors of the Flavivirus methyltransferase. ACS Infect. Dis.,  2015, 1(8), 340-349.
[http://dx.doi.org/10.1021/acsinfecdis.5b00070] [PMID:  26726314] 
[239] 
Brecher, M.; Chen, H.; Liu, B.; Banavali, N.K.; Jones, S.A.; Zhang, J.; Li, Z.; Kramer, L.D.; Li, H. Novel broad spectrum inhibitors targeting the Flavivirus methyltransferase. PLoS One,  2015, 10(6), e0130062.
[http://dx.doi.org/10.1371/journal.pone.0130062] [PMID:  26098995] 
[240] 
Vernekar, S.K.; Qiu, L.; Zhang, J.; Kankanala, J.; Li, H.; Geraghty, R.J.; Wang, Z. 5′-Silylated 3′-1,2,3-triazolyl thymidine analogues as inhibitors of West Nile virus and Dengue virus. J. Med. Chem.,  2015, 58(9), 4016-4028.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00327] [PMID:  25909386] 
[241] 
Verdonk, M.L.; Cole, J.C.; Hartshorn, M.J.; Murray, C.W.; Taylor, R.D. Improved protein-ligand docking using GOLD. Proteins,  2003, 52(4), 609-623.
[http://dx.doi.org/10.1002/prot.10465] [PMID:  12910460] 
[242] 
Luzhkov, V.B.; Selisko, B.; Nordqvist, A.; Peyrane, F.; Decroly, E.; Alvarez, K.; Karlen, A.; Canard, B.; Qvist, J. Virtual screening and bioassay study of novel inhibitors for dengue virus mRNA cap (nucleoside-2'O)-methyltrans-ferase. Bioorg. Med. Chem.,  2007, 15(24), 7795-7802.
[http://dx.doi.org/10.1016/j.bmc.2007.08.049] [PMID:  17888664] 
[243] 
Friesner, R.A.; Banks, J.L.; Murphy, R.B.; Halgren, T.A.; Klicic, J.J.; Mainz, D.T.; Repasky, M.P.; Knoll, E.H.; Shelley, M.; Perry, J.K.; Shaw, D.E.; Francis, P.; Shenkin, P.S. Glide: a new approach for rapid, accurate docking and scoring. Method and assessment of docking accuracy. J. Med. Chem.,  2004, 47(7), 1739-1749.
[http://dx.doi.org/10.1021/jm0306430] [PMID:  15027865] 
[244] 
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem.,  2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID:  15027866] 
[245] 
Podvinec, M.; Lim, S.P.; Schmidt, T.; Scarsi, M.; Wen, D.; Sonntag, L.S.; Sanschagrin, P.; Shenkin, P.S.; Schwede, T. Novel inhibitors of dengue virus methyltransferase: discovery by in vitro-driven virtual screening on a desktop computer grid. J. Med. Chem.,  2010, 53(4), 1483-1495.
[http://dx.doi.org/10.1021/jm900776m] [PMID:  20108931] 
[246] 
Lim, S.P.; Wen, D.; Yap, T.L.; Yan, C.K.; Lescar, J.; Vasudevan, S.G. A scintillation proximity assay for Dengue virus NS5 2′-O-methyltransferase-kinetic and inhibition analyses. Antiviral Res.,  2008, 80(3), 360-369.
[http://dx.doi.org/10.1016/j.antiviral.2008.08.005] [PMID:  18809436] 
[247] 
Benarroch, D.; Egloff, M.P.; Mulard, L.; Guerreiro, C.; Romette, J.L.; Canard, B. A structural basis for the inhibition of the NS5 dengue virus mRNA 2′-O-methyltransferase domain by ribavirin 5′-triphosphate. J. Biol. Chem.,  2004, 279(34), 35638-35643.
[http://dx.doi.org/10.1074/jbc.M400460200] [PMID:  15152003] 
[248] 
Fusco, D.N.; Chung, R.T. Review of current Dengue treatment and therapeutics in development. J. Bioanal. Biomed.,  2014, S8(002).
[http://dx.doi.org/10.4172/1948-593X.S8-002] 
[249] 
Malinoski, F.J.; Hasty, S.E.; Ussery, M.A.; Dalrymple, J.M. Prophylactic ribavirin treatment of dengue type 1 infection in Rhesus monkeys. Antiviral Res.,  1990, 13(3), 139-149.
[http://dx.doi.org/10.1016/0166-3542(90)90029-7] [PMID:  2353804] 
[250] 
Schul, W.; Liu, W.; Xu, H.Y.; Flamand, M.; Vasudevan, S.G. A dengue fever viremia model in mice shows reduction in viral replication and suppression of the inflammatory response after treatment with antiviral drugs. J. Infect. Dis.,  2007, 195(5), 665-674.
[http://dx.doi.org/10.1086/511310] [PMID:  17262707] 
[251] 
Chang, J.; Schul, W.; Butters, T.D.; Yip, A.; Liu, B.; Goh, A.; Lakshminarayana, S.B.; Alonzi, D.; Reinkensmeier, G.; Pan, X.; Qu, X.; Weidner, J.M.; Wang, L.; Yu, W.; Borune, N.; Kinch, M.A.; Rayahin, J.E.; Moriarty, R.; Xu, X.; Shi, P.Y.; Guo, J.T.; Block, T.M. Combination of α-glucosidase inhibitor and ribavirin for the treatment of dengue virus infection in vitro and in vivo. Antiviral Res.,  2011, 89(1), 26-34.
[http://dx.doi.org/10.1016/j.antiviral.2010.11.002] [PMID:  21073903] 
[252] 
Stahla-Beek, H.J.; April, D.G.; Saeedi, B.J.; Hannah, A.M.; Keenan, S.M.; Geiss, B.J. Identification of a novel antiviral inhibitor of the Flavivirus guanylyltransferase enzyme. J. Virol.,  2012, 86(16), 8730-8739.
[http://dx.doi.org/10.1128/JVI.00384-12] [PMID:  22674988] 
[253] 
Bullard, K.M.; Gullberg, R.C.; Soltani, E.; Steel, J.J.; Geiss, B.J.; Keenan, S.M. Murine efficacy and pharmacokinetic evaluation of the Flaviviral NS5 capping enzyme 2-thioxothiazolidin-4-one inhibitor BG-323. PLoS One,  2015, 10(6), e0130083.
[http://dx.doi.org/10.1371/journal.pone.0130083] [PMID:  26075394] 
[254] 
Morris, G.M.; Huey, R.; Lindstrom, W.; Sanner, M.F.; Belew, R.K.; Goodsell, D.S.; Olson, A.J. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J. Comput. Chem.,  2009, 30(16), 2785-2791.
[http://dx.doi.org/10.1002/jcc.21256] [PMID:  19399780] 
[255] 
Milani, M.; Mastrangelo, E.; Bollati, M.; Selisko, B.; Decroly, E.; Bouvet, M.; Canard, B.; Bolognesi, M. Flaviviral methyltransferase/RNA interaction: structural basis for enzyme inhibition. Antiviral Res.,  2009, 83(1), 28-34.
[http://dx.doi.org/10.1016/j.antiviral.2009.03.001] [PMID:  19501254] 
[256] 
Berendsen, H.J.C.; van der Spoel, D.; van Drunen, R. GROMACS: A message-passing parallel molecular dynamics implementation. Comput. Phys. Commun.,  1995, 91(1), 43-56.
[http://dx.doi.org/10.1016/0010-4655(95)00042-E] 
[257] 
Benmansour, F.; Trist, I.; Coutard, B.; Decroly, E.; Querat, G.; Brancale, A.; Barral, K. Discovery of novel Dengue virus NS5 methyltransferase non-nucleoside inhibitors by fragment-based drug design. Eur. J. Med. Chem.,  2017, 125, 865-880.
[http://dx.doi.org/10.1016/j.ejmech.2016.10.007] [PMID:  27750202] 
[258] 
Malet, H.; Massé, N.; Selisko, B.; Romette, J.L.; Alvarez, K.; Guillemot, J.C.; Tolou, H.; Yap, T.L.; Vasudevan, S.; Lescar, J.; Canard, B. The flavivirus polymerase as a target for drug discovery. Antiviral Res.,  2008, 80(1), 23-35.
[http://dx.doi.org/10.1016/j.antiviral.2008.06.007] [PMID:  18611413] 
[259] 
Choi, K.H. Viral polymerases. Adv. Exp. Med. Biol.,  2012, 726, 267-304.
[http://dx.doi.org/10.1007/978-1-4614-0980-9_12] [PMID:  22297518] 
[260] 
Poch, O.; Sauvaget, I.; Delarue, M.; Tordo, N. Identification of four conserved motifs among the RNA-dependent polymerase encoding elements. EMBO J.,  1989, 8(12), 3867-3874.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb08565.x] [PMID:  2555175] 
[261] 
Wu, J.; Liu, W.; Gong, P. A structural overview of RNA-dependent RNA polymerases from the Flaviviridae family. Int. J. Mol. Sci.,  2015, 16(6), 12943-12957.
[http://dx.doi.org/10.3390/ijms160612943] [PMID:  26062131] 
[262] 
De Clercq, E.; Neyts, J. Antiviral agents acting as DNA or RNA chain terminators. Handb. Exp. Pharmacol.,  2009, (189), 53-84.
[http://dx.doi.org/10.1007/978-3-540-79086-0_3] [PMID:  19048197] 
[263] 
Luo, G.; Hamatake, R.K.; Mathis, D.M.; Racela, J.; Rigat, K.L.; Lemm, J.; Colonno, R.J. De novo initiation of RNA synthesis by the RNA-dependent RNA polymerase (NS5B) of hepatitis C virus. J. Virol.,  2000, 74(2), 851-863.
[http://dx.doi.org/10.1128/JVI.74.2.851-863.2000] [PMID:  10623748] 
[264] 
Surana, P.; Satchidanandam, V.; Nair, D.T. RNA-dependent RNA polymerase of Japanese encephalitis virus binds the initiator nucleotide GTP to form a mechanistically important pre-initiation state. Nucleic Acids Res.,  2014, 42(4), 2758-2773.
[http://dx.doi.org/10.1093/nar/gkt1106] [PMID:  24293643] 
[265] 
Romette, J.; Selisko, B.; Egloff, M.; Benarroch, D.; Canard, B. Active truncated form of the RNA polymerase of flavivirus. united states patent u.s. patent 20050048472,, 2005.
[266] 
Yap, T.L.; Xu, T.; Chen, Y.L.; Malet, H.; Egloff, M.P.; Canard, B.; Vasudevan, S.G.; Lescar, J. Crystal structure of the Dengue virus RNA-dependent RNA polymerase catalytic domain at 1.85-angstrom resolution. J. Virol.,  2007, 81(9), 4753-4765.
[http://dx.doi.org/10.1128/JVI.02283-06] [PMID:  17301146] 
[267] 
Vernachio, J.H.; Bleiman, B.; Bryant, K.D.; Chamberlain, S.; Hunley, D.; Hutchins, J.; Ames, B.; Gorovits, E.; Ganguly, B.; Hall, A.; Kolykhalov, A.; Liu, Y.; Muhammad, J.; Raja, N.; Walters, C.R.; Wang, J.; Williams, K.; Patti, J.M.; Henson, G.; Madela, K.; Aljarah, M.; Gilles, A.; McGuigan, C. INX-08189, a phosphoramidate prodrug of 6-O-methyl-2′-C-methyl guanosine, is a potent inhibitor of hepatitis C virus replication with excellent pharmacokinetic and pharmacodynamic properties. Antimicrob. Agents Chemother.,  2011, 55(5), 1843-1851.
[http://dx.doi.org/10.1128/AAC.01335-10] [PMID:  21357300] 
[268] 
Migliaccio, G.; Tomassini, J.E.; Carroll, S.S.; Tomei, L.; Altamura, S.; Bhat, B.; Bartholomew, L.; Bosserman, M.R.; Ceccacci, A.; Colwell, L.F.; Cortese, R.; De Francesco, R.; Eldrup, A.B.; Getty, K.L.; Hou, X.S.; LaFemina, R.L.; Ludmerer, S.W.; MacCoss, M.; McMasters, D.R.; Stahlhut, M.W.; Olsen, D.B.; Hazuda, D.J.; Flores, O.A. Characterization of resistance to non-obligate chain-terminating ribonucleoside analogs that inhibit hepatitis C virus replication in vitro. J. Biol. Chem.,  2003, 278(49), 49164-49170.
[http://dx.doi.org/10.1074/jbc.M305041200] [PMID:  12966103] 
[269] 
Chen, Y.L.; Yokokawa, F.; Shi, P.Y. The search for nucleoside/nucleotide analog inhibitors of Dengue virus. Antiviral Res.,  2015, 122, 12-19.
[http://dx.doi.org/10.1016/j.antiviral.2015.07.010] [PMID:  26241002] 
[270] 
Yeo, K.L.; Chen, Y.L.; Xu, H.Y.; Dong, H.; Wang, Q.Y.; Yokokawa, F.; Shi, P.Y. Synergistic suppression of Dengue virus replication using a combination of nucleoside analogs and nucleoside synthesis inhibitors. Antimicrob. Agents Chemother.,  2015, 59(4), 2086-2093.
[http://dx.doi.org/10.1128/AAC.04779-14] [PMID:  25624323] 
[271] 
Lee, J.C.; Tseng, C.K.; Wu, Y.H.; Kaushik-Basu, N.; Lin, C.K.; Chen, W.C.; Wu, H.N. Characterization of the activity of 2′-C-methylcytidine against dengue virus replication. Antiviral Res.,  2015, 116, 1-9.
[http://dx.doi.org/10.1016/j.antiviral.2015.01.002] [PMID:  25614455] 
[272] 
Eyer, L.; Nencka, R.; Huvarová, I.; Palus, M.; Joao Alves, M.; Gould, E.A.; De Clercq, E.; Růžek, D. Nucleoside Inhibitors of Zika Virus. J. Infect. Dis.,  2016, 214(5), 707-711.
[http://dx.doi.org/10.1093/infdis/jiw226] [PMID:  27234417] 
[273] 
Potisopon, S.; Ferron, F.; Fattorini, V.; Selisko, B.; Canard, B. Substrate selectivity of Dengue and Zika virus NS5 polymerase towards 2′-modified nucleotide analogues. Antiviral Res.,  2017, 140, 25-36.
[http://dx.doi.org/10.1016/j.antiviral.2016.12.021] [PMID:  28041959] 
[274] 
Denning, J.; Cornpropst, M.; Flach, S.D.; Berrey, M.M.; Symonds, W.T. Pharmacokinetics, safety, and tolerability of GS-9851, a nucleotide analog polymerase inhibitor for hepatitis C virus, following single ascending doses in healthy subjects. Antimicrob. Agents Chemother.,  2013, 57(3), 1201-1208.
[http://dx.doi.org/10.1128/AAC.01262-12] [PMID:  23262999] 
[275] 
Murakami, E.; Tolstykh, T.; Bao, H.; Niu, C.; Steuer, H.M.; Bao, D.; Chang, W.; Espiritu, C.; Bansal, S.; Lam, A.M.; Otto, M.J.; Sofia, M.J.; Furman, P.A. Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem.,  2010, 285(45), 34337-34347.
[http://dx.doi.org/10.1074/jbc.M110.161802] [PMID:  20801890] 
[276] 
Gan, C.S.; Lim, S.K.; Chee, C.F.; Yusof, R.; Heh, C.H. Sofosbuvir as treatment against dengue? Chem. Biol. Drug Des., 2017.
[http://dx.doi.org/10.1111/cbdd.13091]] [PMID:  28834304] 
[277] 
Xu, H.T.; Colby-Germinario, S.P.; Hassounah, S.A.; Fogarty, C.; Osman, N.; Palanisamy, N.; Han, Y.; Oliveira, M.; Quan, Y.; Wainberg, M.A. Evaluation of Sofosbuvir (β-D-2′-deoxy-2′-α-fluoro-2′-β-C-methyluridine) as an inhibitor of Dengue virus replication<sup/>. Sci. Rep.,  2017, 7(1), 6345.
[http://dx.doi.org/10.1038/s41598-017-06612-2] [PMID:  28740124] 
[278] 
Nguyen, N.M.; Tran, C.N.; Phung, L.K.; Duong, K.T. Huynh, Hle.A.; Farrar, J.; Nguyen, Q.T.; Tran, H.T.; Nguyen, C.V.; Merson, L.; Hoang, L.T.; Hibberd, M.L.; Aw, P.P.; Wilm, A.; Nagarajan, N.; Nguyen, D.T.; Pham, M.P.; Nguyen, T.T.; Javanbakht, H.; Klumpp, K.; Hammond, J.; Petric, R.; Wolbers, M.; Nguyen, C.T.; Simmons, C.P. A randomized, double-blind placebo controlled trial of balapiravir, a polymerase inhibitor, in adult dengue patients. J. Infect. Dis.,  2013, 207(9), 1442-1450.
[http://dx.doi.org/10.1093/infdis/jis470] [PMID:  22807519] 
[279] 
Yin, Z.; Chen, Y.L.; Schul, W.; Wang, Q.Y.; Gu, F.; Duraiswamy, J.; Kondreddi, R.R.; Niyomrattanakit, P.; Lakshminarayana, S.B.; Goh, A.; Xu, H.Y.; Liu, W.; Liu, B.; Lim, J.Y.; Ng, C.Y.; Qing, M.; Lim, C.C.; Yip, A.; Wang, G.; Chan, W.L.; Tan, H.P.; Lin, K.; Zhang, B.; Zou, G.; Bernard, K.A.; Garrett, C.; Beltz, K.; Dong, M.; Weaver, M.; He, H.; Pichota, A.; Dartois, V.; Keller, T.H.; Shi, P.Y. An adenosine nucleoside inhibitor of Dengue virus. Proc. Natl. Acad. Sci. USA,  2009, 106(48), 20435-20439.
[http://dx.doi.org/10.1073/pnas.0907010106] [PMID:  19918064] 
[280] 
Chen, Y.L.; Yin, Z.; Lakshminarayana, S.B.; Qing, M.; Schul, W.; Duraiswamy, J.; Kondreddi, R.R.; Goh, A.; Xu, H.Y.; Yip, A.; Liu, B.; Weaver, M.; Dartois, V.; Keller, T.H.; Shi, P.Y. Inhibition of dengue virus by an ester prodrug of an adenosine analog. Antimicrob. Agents Chemother.,  2010, 54(8), 3255-3261.
[http://dx.doi.org/10.1128/AAC.00397-10] [PMID:  20516277] 
[281] 
Wu, R.; Smidansky, E.D.; Oh, H.S.; Takhampunya, R.; Padmanabhan, R.; Cameron, C.E.; Peterson, B.R. Synthesis of a 6-methyl-7-deaza analogue of adenosine that potently inhibits replication of polio and dengue viruses. J. Med. Chem.,  2010, 53(22), 7958-7966.
[http://dx.doi.org/10.1021/jm100593s] [PMID:  20964406] 
[282] 
Eyer, L.; Zouharová, D.; Širmarová, J.; Fojtíková, M.; Štefánik, M.; Haviernik, J.; Nencka, R.; de Clercq, E.; Růžek, D. Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses. Antiviral Res.,  2017, 142, 63-67.
[http://dx.doi.org/10.1016/j.antiviral.2017.03.012] [PMID:  28336346] 
[283] 
Julander, J.G.; Bantia, S.; Taubenheim, B.R.; Minning, D.M.; Kotian, P.; Morrey, J.D.; Smee, D.F.; Sheridan, W.P.; Babu, Y.S. BCX4430, a novel nucleoside analog, effectively treats yellow fever in a Hamster model. Antimicrob. Agents Chemother.,  2014, 58(11), 6607-6614.
[http://dx.doi.org/10.1128/AAC.03368-14] [PMID:  25155605] 
[284] 
Julander, J.G.; Siddharthan, V.; Evans, J.; Taylor, R.; Tolbert, K.; Apuli, C.; Stewart, J.; Collins, P.; Gebre, M.; Neilson, S.; Van Wettere, A.; Lee, Y.M.; Sheridan, W.P.; Morrey, J.D.; Babu, Y.S. Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model. Antiviral Res.,  2017, 137, 14-22.
[http://dx.doi.org/10.1016/j.antiviral.2016.11.003] [PMID:  27838352] 
[285] 
Taylor, R.; Kotian, P.; Warren, T.; Panchal, R.; Bavari, S.; Julander, J.; Dobo, S.; Rose, A.; El-Kattan, Y.; Taubenheim, B.; Babu, Y.; Sheridan, W.P. BCX4430 - A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease. J. Infect. Public Health,  2016, 9(3), 220-226.
[http://dx.doi.org/10.1016/j.jiph.2016.04.002] [PMID:  27095300] 
[286] 
Warren, T.K.; Wells, J.; Panchal, R.G.; Stuthman, K.S.; Garza, N.L.; Van Tongeren, S.A.; Dong, L.; Retterer, C.J.; Eaton, B.P.; Pegoraro, G.; Honnold, S.; Bantia, S.; Kotian, P.; Chen, X.; Taubenheim, B.R.; Welch, L.S.; Minning, D.M.; Babu, Y.S.; Sheridan, W.P.; Bavari, S. Protection against filovirus diseases by a novel broad-spectrum nucleoside analogue BCX4430. Nature,  2014, 508(7496), 402-405.
[http://dx.doi.org/10.1038/nature13027] [PMID:  24590073] 
[287] 
Tichý, M.; Pohl, R.; Xu, H.Y.; Chen, Y.L.; Yokokawa, F.; Shi, P.Y.; Hocek, M. Synthesis and antiviral activity of 4,6-disubstituted pyrimido[4,5-b]indole ribonucleosides. Bioorg. Med. Chem.,  2012, 20(20), 6123-6133.
[http://dx.doi.org/10.1016/j.bmc.2012.08.021] [PMID:  22985963] 
[288] 
Tichý, M.; Pohl, R.; Tloušt’ová, E.; Weber, J.; Bahador, G.; Lee, Y.J.; Hocek, M. Synthesis and biological activity of benzo-fused 7-deazaadenosine analogues. 5- and 6-substituted 4-amino- or 4-alkylpyrimido[4,5-b]indole ribonucleosides. Bioorg. Med. Chem.,  2013, 21(17), 5362-5372.
[http://dx.doi.org/10.1016/j.bmc.2013.06.011] [PMID:  23827234] 
[289] 
Chatelain, G.; Debing, Y.; De Burghgraeve, T.; Zmurko, J.; Saudi, M.; Rozenski, J.; Neyts, J.; Van Aerschot, A. In search of flavivirus inhibitors: evaluation of different tritylated nucleoside analogues. Eur. J. Med. Chem.,  2013, 65, 249-255.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.034] [PMID:  23721953] 
[290] 
De Burghgraeve, T.; Selisko, B.; Kaptein, S.; Chatelain, G.; Leyssen, P.; Debing, Y.; Jacobs, M.; Van Aerschot, A.; Canard, B.; Neyts, J. 3′,5'Di-O-trityluridine inhibits in vitro flavivirus replication. Antiviral Res.,  2013, 98(2), 242-247.
[http://dx.doi.org/10.1016/j.antiviral.2013.01.011] [PMID:  23470860] 
[291] 
McGuigan, C.; Serpi, M.; Slusarczyk, M.; Ferrari, V.; Pertusati, F.; Meneghesso, S.; Derudas, M.; Farleigh, L.; Zanetta, P.; Bugert, J. Anti-flavivirus activity of different tritylated pyrimidine and purine nucleoside analogues. Chem. Open,  2016, 5(3), 227-235.
[http://dx.doi.org/10.1002/open.201500216] [PMID:  27551659] 
[292] 
Saudi, M.; Zmurko, J.; Kaptein, S.; Rozenski, J.; Neyts, J.; Van Aerschot, A. In search of Flavivirus inhibitors part 2: tritylated, diphenylmethylated and other alkylated nucleoside analogues. Eur. J. Med. Chem.,  2014, 76, 98-109.
[http://dx.doi.org/10.1016/j.ejmech.2014.02.011] [PMID:  24583349] 
[293] 
Yin, Z.; Chen, Y.L.; Kondreddi, R.R.; Chan, W.L.; Wang, G.; Ng, R.H.; Lim, J.Y.; Lee, W.Y.; Jeyaraj, D.A.; Niyomrattanakit, P.; Wen, D.; Chao, A.; Glickman, J.F.; Voshol, H.; Mueller, D.; Spanka, C.; Dressler, S.; Nilar, S.; Vasudevan, S.G.; Shi, P.Y.; Keller, T.H. N-sulfonylanthranilic acid derivatives as allosteric inhibitors of dengue viral RNA-dependent RNA polymerase. J. Med. Chem.,  2009, 52(24), 7934-7937.
[http://dx.doi.org/10.1021/jm901044z] [PMID:  20014868] 
[294] 
Niyomrattanakit, P.; Chen, Y.L.; Dong, H.; Yin, Z.; Qing, M.; Glickman, J.F.; Lin, K.; Mueller, D.; Voshol, H.; Lim, J.Y.; Nilar, S.; Keller, T.H.; Shi, P.Y. Inhibition of dengue virus polymerase by blocking of the RNA tunnel. J. Virol.,  2010, 84(11), 5678-5686.
[http://dx.doi.org/10.1128/JVI.02451-09] [PMID:  20237086] 
[295] 
Noble, C.G.; Lim, S.P.; Chen, Y.L.; Liew, C.W.; Yap, L.; Lescar, J.; Shi, P.Y. Conformational flexibility of the Dengue virus RNA-dependent RNA polymerase revealed by a complex with an inhibitor. J. Virol.,  2013, 87(9), 5291-5295.
[http://dx.doi.org/10.1128/JVI.00045-13] [PMID:  23408636] 
[296] 
Noble, C.G.; Lim, S.P.; Arora, R.; Yokokawa, F.; Nilar, S.; Seh, C.C.; Wright, S.K.; Benson, T.E.; Smith, P.W.; Shi, P.Y. A conserved pocket in the Dengue virus polymerase identified through fragment-based screening. J. Biol. Chem.,  2016, 291(16), 8541-8548.
[http://dx.doi.org/10.1074/jbc.M115.710731] [PMID:  26872970] 
[297] 
Yokokawa, F.; Nilar, S.; Noble, C.G.; Lim, S.P.; Rao, R.; Tania, S.; Wang, G.; Lee, G.; Hunziker, J.; Karuna, R.; Manjunatha, U.; Shi, P.Y.; Smith, P.W. Discovery of potent non-nucleoside inhibitors of Dengue viral RNA-dependent RNA polymerase from a fragment hit using structure-based drug design. J. Med. Chem.,  2016, 59(8), 3935-3952.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00143] [PMID:  26984786] 
[298] 
Lim, S.P.; Noble, C.G.; Seh, C.C.; Soh, T.S.; El Sahili, A.; Chan, G.K.; Lescar, J.; Arora, R.; Benson, T.; Nilar, S.; Manjunatha, U.; Wan, K.F.; Dong, H.; Xie, X.; Shi, P.Y.; Yokokawa, F. Potent allosteric Dengue virus NS5 polymerase inhibitors: mechanism of action and resistance profiling. PLoS Pathog.,  2016, 12(8), e1005737.
[http://dx.doi.org/10.1371/journal.ppat.1005737] [PMID:  27500641] 
[299] 
Tarantino, D.; Cannalire, R.; Mastrangelo, E.; Croci, R.; Querat, G.; Barreca, M.L.; Bolognesi, M.; Manfroni, G.; Cecchetti, V.; Milani, M. Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor. Antiviral Res.,  2016, 134, 226-235.
[http://dx.doi.org/10.1016/j.antiviral.2016.09.007] [PMID:  27649989] 
[300] 
Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and Dengue virus. Biochem. J.,  2012, 443(3), 851-856.
[http://dx.doi.org/10.1042/BJ20120150] [PMID:  22417684] 
[301] 
Tay, M.Y.; Fraser, J.E.; Chan, W.K.; Moreland, N.J.; Rathore, A.P.; Wang, C.; Vasudevan, S.G.; Jans, D.A. Nuclear localization of Dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res.,  2013, 99(3), 301-306.
[http://dx.doi.org/10.1016/j.antiviral.2013.06.002] [PMID:  23769930] 
[302] 
Fraser, J.E.; Watanabe, S.; Wang, C.; Chan, W.K.; Maher, B.; Lopez-Denman, A.; Hick, C.; Wagstaff, K.M.; Mackenzie, J.M.; Sexton, P.M.; Vasudevan, S.G.; Jans, D.A. A nuclear transport inhibitor that modulates the unfolded protein response and provides in vivo protection against lethal dengue virus infection. J. Infect. Dis.,  2014, 210(11), 1780-1791.
[http://dx.doi.org/10.1093/infdis/jiu319] [PMID:  24903662] 
[303] 
Vincetti, P.; Caporuscio, F.; Kaptein, S.; Gioiello, A.; Mancino, V.; Suzuki, Y.; Yamamoto, N.; Crespan, E.; Lossani, A.; Maga, G.; Rastelli, G.; Castagnolo, D.; Neyts, J.; Leyssen, P.; Costantino, G.; Radi, M. Discovery of multitarget antivirals acting on both the Dengue virus NS5-NS3 interaction and the host Src/Fyn kinases. J. Med. Chem.,  2015, 58(12), 4964-4975.
[http://dx.doi.org/10.1021/acs.jmedchem.5b00108] [PMID:  26039671] 
[304] 
Carocci, M.; Hinshaw, S.M.; Rodgers, M.A.; Villareal, V.A.; Burri, D.J.; Pilankatta, R.; Maharaj, N.P.; Gack, M.U.; Stavale, E.J.; Warfield, K.L.; Yang, P.L. The bioactive lipid 4-hydroxyphenyl retinamide inhibits flavivirus replication. Antimicrob. Agents Chemother.,  2015, 59(1), 85-95.
[http://dx.doi.org/10.1128/AAC.04177-14] [PMID:  25313218] 
[305] 
Thenin-Houssier, S.; Valente, S.T.S. HIV-1 capsid inhibitors as antiretroviral agents. Curr. HIV Res.,  2016, 14(3), 270-282.
[http://dx.doi.org/10.2174/1570162X14999160224103555] [PMID:  26957201] 
[306] 
w.h.o.neglected tropical diseases − summary, http://www.who.int/neglected_diseases/diseases/summary/en/
Rights & Permissions Print Cite
Article Metrics
30
Journal Information
For Authors
For Editors
For Reviewers
Explore Articles
Open Access
Open Access Articles
For Visitors
DOI https://dx.doi.org/10.2174/0929867326666181204155336	Print ISSN 0929-8673
Publisher Name Bentham Science Publisher	Online ISSN 1875-533X
当代药物化学

发现登革热病毒抑制剂

摘要

当代药物化学

发现登革热病毒抑制剂

摘要 Play Pause

Related Journals

Related Books

摘要
