Viral Entry Inhibitors Targeting Six-Helical Bundle Core against
Highly Pathogenic Enveloped Viruses with Class I Fusion Proteins

Jing       Pu; Joey    Tianyi    Zhou; Ping       Liu; Fei       Yu; Xiaoyang       He; Lu       Lu; Shibo       Jiang
Abstract

Type Ⅰ enveloped viruses bind to cell receptors through surface glycoproteins to initiate infection or undergo receptor-mediated endocytosis and initiate membrane fusion in the acidic environment of endocytic compartments, releasing genetic material into the cell. In the process of membrane fusion, envelope protein exposes fusion peptide, followed by an insertion into the cell membrane or endosomal membrane. Further conformational changes ensue in which the type 1 envelope protein forms a typical six-helix bundle structure, shortening the distance between viral and cell membranes so that fusion can occur. Entry inhibitors targeting viral envelope proteins, or host factors, are effective antiviral agents and have been widely studied. Some have been used clinically, such as T20 and Maraviroc for human immunodeficiency virus 1 (HIV-1) or Myrcludex B for hepatitis D virus (HDV). This review focuses on entry inhibitors that target the six-helical bundle core against highly pathogenic enveloped viruses with class I fusion proteins, including retroviruses, coronaviruses, influenza A viruses, paramyxoviruses, and filoviruses.
Keywords: Entry inhibitor, 6-HB, class I fusion proteins, highly pathogenic, enveloped viruses, COVID-19.
[1] 
Chan, D.C.; Fass, D.; Berger, J.M.; Kim, P.S. Core structure of gp41 from the HIV envelope glycoprotein. Cell,  1997, 89(2), 263-273.
[http://dx.doi.org/10.1016/S0092-8674(00)80205-6] [PMID:  9108481] 
[2] 
Xu, W.; Pu, J.; Su, S.; Hua, C.; Su, X.; Wang, Q.; Jiang, S.; Lu, L. Revisiting the mechanism of enfuvirtide and designing an analog with improved fusion inhibitory activity by targeting triple sites in gp41. AIDS,  2019, 33(10), 1545-1555.
[http://dx.doi.org/10.1097/QAD.0000000000002208] [PMID:  30932963] 
[3] 
Xia, S.; Yan, L.; Xu, W.; Agrawal, A.S.; Algaissi, A.; Tseng, C.K.; Wang, Q.; Du, L.; Tan, W.; Wilson, I.A.; Jiang, S.; Yang, B.; Lu, L. A pan-coronavirus fusion inhibitor targeting the HR1 domain of human coronavirus spike. Sci. Adv.,  2019, 5(4)eaav4580
[http://dx.doi.org/10.1126/sciadv.aav4580] [PMID:  30989115] 
[4] 
Bossart, K.N.; Wang, L.F.; Flora, M.N.; Chua, K.B.; Lam, S.K.; Eaton, B.T.; Broder, C.C. Membrane fusion tropism and heterotypic functional activities of the Nipah virus and Hendra virus envelope glycoproteins. J. Virol.,  2002, 76(22), 11186-11198.
[http://dx.doi.org/10.1128/JVI.76.22.11186-11198.2002] [PMID:  12388678] 
[5] 
Miller, E.H.; Harrison, J.S.; Radoshitzky, S.R.; Higgins, C.D.; Chi, X.; Dong, L.; Kuhn, J.H.; Bavari, S.; Lai, J.R.; Chandran, K. Inhibition of Ebola virus entry by a C-peptide targeted to endosomes. J. Biol. Chem.,  2011, 286(18), 15854-15861.
[http://dx.doi.org/10.1074/jbc.M110.207084] [PMID:  21454542] 
[6] 
Jiang, S.; Lu, H.; Liu, S.; Zhao, Q.; He, Y.; Debnath, A.K. N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion. Antimicrob. Agents Chemother.,  2004, 48(11), 4349-4359.
[http://dx.doi.org/10.1128/AAC.48.11.4349-4359.2004] [PMID:  15504864] 
[7] 
Jin, B.S.; Lee, W.K.; Ahn, K.; Lee, M.K.; Yu, Y.G. High-throughput screening method of inhibitors that block the interaction between 2 helical regions of HIV-1 gp41. J. Biomol. Screen.,  2005, 10(1), 13-19.
[http://dx.doi.org/10.1177/1087057104269726] [PMID:  15695339] 
[8] 
Liu, S.; Lu, H.; Niu, J.; Xu, Y.; Wu, S.; Jiang, S. Different from the HIV fusion inhibitor C34, the anti-HIV drug Fuzeon (T-20) inhibits HIV-1 entry by targeting multiple sites in gp41 and gp120. J. Biol. Chem.,  2005, 280(12), 11259-11273.
[http://dx.doi.org/10.1074/jbc.M411141200] [PMID:  15640162] 
[9] 
Liu, S.; Jing, W.; Cheung, B.; Lu, H.; Sun, J.; Yan, X.; Niu, J.; Farmar, J.; Wu, S.; Jiang, S. HIV gp41 C-terminal heptad repeat contains multifunctional domains. Relation to mechanisms of action of anti-HIV peptides. J. Biol. Chem.,  2007, 282(13), 9612-9620.
[http://dx.doi.org/10.1074/jbc.M609148200] [PMID:  17276993] 
[10] 
Zhang, X.; Ding, X.; Zhu, Y.; Chong, H.; Cui, S.; He, J.; Wang, X.; He, Y. Structural and functional characterization of HIV-1 cell fusion inhibitor T20. AIDS,  2019, 33(1), 1-11.
[http://dx.doi.org/10.1097/QAD.0000000000001979] [PMID:  30096076] 
[11] 
Fumakia, M.; Yang, S.; Gu, J.; Ho, E.A. Protein/peptide-based entry/fusion inhibitors as anti-HIV therapies: Challenges and future direction. Rev. Med. Virol.,  2016, 26(1), 4-20.
[http://dx.doi.org/10.1002/rmv.1853] [PMID:  26308574] 
[12] 
Pérez-Alvarez, L.; Carmona, R.; Ocampo, A.; Asorey, A.; Miralles, C.; Pérez de Castro, S.; Pinilla, M.; Contreras, G.; Taboada, J.A.; Nájera, R. Long-term monitoring of genotypic and phenotypic resistance to T20 in treated patients infected with HIV-1. J. Med. Virol.,  2006, 78(2), 141-147.
[http://dx.doi.org/10.1002/jmv.20520] [PMID:  16372284] 
[13] 
Ball, R.A.; Kinchelow, T. ISR Substudy Group. Injection site reactions with the HIV-1 fusion inhibitor enfuvirtide. J. Am. Acad. Dermatol.,  2003, 49(5), 826-831.
[http://dx.doi.org/10.1016/S0190-9622(03)02099-1] [PMID:  14576660] 
[14] 
Maggi, P.; Ladisa, N.; Cinori, E.; Altobella, A.; Pastore, G.; Filotico, R. Cutaneous injection site reactions to long-term therapy with enfuvirtide. J. Antimicrob. Chemother.,  2004, 53(4), 678-681.
[http://dx.doi.org/10.1093/jac/dkh141] [PMID:  14985276] 
[15] 
Lalezari, J.P.; Bellos, N.C.; Sathasivam, K.; Richmond, G.J.; Cohen, C.J.; Myers, R.A., Jr; Henry, D.H.; Raskino, C.; Melby, T.; Murchison, H.; Zhang, Y.; Spence, R.; Greenberg, M.L.; Demasi, R.A.; Miralles, G.D. T1249-102 Study Group. T-1249 retains potent antiretroviral activity in patients who had experienced virological failure while on an enfuvirtide-containing treatment regimen. J. Infect. Dis.,  2005, 191(7), 1155-1163.
[http://dx.doi.org/10.1086/427993] [PMID:  15747252] 
[16] 
Eron, J.J.; Gulick, R.M.; Bartlett, J.A.; Merigan, T.; Arduino, R.; Kilby, J.M.; Yangco, B.; Diers, A.; Drobnes, C.; DeMasi, R.; Greenberg, M.; Melby, T.; Raskino, C.; Rusnak, P.; Zhang, Y.; Spence, R.; Miralles, G.D. Short-term safety and antiretroviral activity of T-1249, a second-generation fusion inhibitor of HIV. J. Infect. Dis.,  2004, 189(6), 1075-1083.
[http://dx.doi.org/10.1086/381707] [PMID:  14999611] 
[17] 
Eggink, D.; Baldwin, C.E.; Deng, Y.; Langedijk, J.P.; Lu, M.; Sanders, R.W.; Berkhout, B. Selection of T1249-resistant human immunodeficiency virus type 1 variants. J. Virol.,  2008, 82(13), 6678-6688.
[http://dx.doi.org/10.1128/JVI.00352-08] [PMID:  18434391] 
[18] 
Dwyer, J.J.; Wilson, K.L.; Davison, D.K.; Freel, S.A.; Seedorff, J.E.; Wring, S.A.; Tvermoes, N.A.; Matthews, T.J.; Greenberg, M.L.; Delmedico, M.K. Design of helical, oligomeric HIV-1 fusion inhibitor peptides with potent activity against enfuvirtide-resistant virus. Proc. Natl. Acad. Sci. USA,  2007, 104(31), 12772-12777.
[http://dx.doi.org/10.1073/pnas.0701478104] [PMID:  17640899] 
[19] 
He, Y.; Xiao, Y.; Song, H.; Liang, Q.; Ju, D.; Chen, X.; Lu, H.; Jing, W.; Jiang, S.; Zhang, L. Design and evaluation of sifuvirtide, a novel HIV-1 fusion inhibitor. J. Biol. Chem.,  2008, 283(17), 11126-11134.
[http://dx.doi.org/10.1074/jbc.M800200200] [PMID:  18303020] 
[20] 
Yao, X.; Chong, H.; Zhang, C.; Waltersperger, S.; Wang, M.; Cui, S.; He, Y. Broad antiviral activity and crystal structure of HIV-1 fusion inhibitor sifuvirtide. J. Biol. Chem.,  2012, 287(9), 6788-6796.
[http://dx.doi.org/10.1074/jbc.M111.317883] [PMID:  22228771] 
[21] 
Liu, Z.; Shan, M.; Li, L.; Lu, L.; Meng, S.; Chen, C.; He, Y.; Jiang, S.; Zhang, L. In vitro selection and characterization of HIV-1 variants with increased resistance to sifuvirtide, a novel HIV-1 fusion inhibitor. J. Biol. Chem.,  2011, 286(5), 3277-3287.
[http://dx.doi.org/10.1074/jbc.M110.199323] [PMID:  21098485] 
[22] 
Martin-Carbonero, L. Discontinuation of the clinical development of fusion inhibitor T-1249. AIDS Rev.,  2004, 6(1), 61.
[PMID:  15168742] 
[23] 
Otaka, A.; Nakamura, M.; Nameki, D.; Kodama, E.; Uchiyama, S.; Nakamura, S.; Nakano, H.; Tamamura, H.; Kobayashi, Y.; Matsuoka, M.; Fujii, N. Remodeling of gp41-C34 peptide leads to highly effective inhibitors of the fusion of HIV-1 with target cells. Angew. Chem. Int. Ed. Engl.,  2002, 41(16), 2937-2940.
[http://dx.doi.org/10.1002/1521-3773(20020816)41:16< 2937:AID-ANIE2937>3.0.CO;2-J] [PMID:  12203417] 
[24] 
Su, S.; Rasquinha, G.; Du, L.; Wang, Q.; Xu, W.; Li, W.; Lu, L.; Jiang, S. A peptide-based hiv-1 fusion inhibitor with two tail-anchors and palmitic acid exhibits substantially improved In Vitro and Ex Vivo Anti-HIV-1 activity and prolonged In Vivo half-life. Molecules,  2019, 24(6)E1134
[http://dx.doi.org/10.3390/molecules24061134] [PMID:  30901967] 
[25] 
Ujike, M.; Nishikawa, H.; Otaka, A.; Yamamoto, N.; Yamamoto, N.; Matsuoka, M.; Kodama, E.; Fujii, N.; Taguchi, F. Heptad repeat-derived peptides block protease-mediated direct entry from the cell surface of severe acute respiratory syndrome coronavirus but not entry via the endosomal pathway. J. Virol.,  2008, 82(1), 588-592.
[http://dx.doi.org/10.1128/JVI.01697-07] [PMID:  17942557] 
[26] 
Xie, D.; Yao, C.; Wang, L.; Min, W.; Xu, J.; Xiao, J.; Huang, M.; Chen, B.; Liu, B.; Li, X.; Jiang, H. An albumin-conjugated peptide exhibits potent anti-HIV activity and long in vivo half-life. Antimicrob. Agents Chemother.,  2010, 54(1), 191-196.
[http://dx.doi.org/10.1128/AAC.00976-09] [PMID:  19858258] 
[27] 
Chong, H.; Yao, X.; Qiu, Z.; Qin, B.; Han, R.; Waltersperger, S.; Wang, M.; Cui, S.; He, Y. Discovery of critical residues for viral entry and inhibition through structural Insight of HIV-1 fusion inhibitor CP621-652. J. Biol. Chem.,  2012, 287(24), 20281-20289.
[http://dx.doi.org/10.1074/jbc.M112.354126] [PMID:  22511760] 
[28] 
Ingallinella, P.; Bianchi, E.; Ladwa, N.A.; Wang, Y.J.; Hrin, R.; Veneziano, M.; Bonelli, F.; Ketas, T.J.; Moore, J.P.; Miller, M.D.; Pessi, A. Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc. Natl. Acad. Sci. USA,  2009, 106(14), 5801-5806.
[http://dx.doi.org/10.1073/pnas.0901007106] [PMID:  19297617] 
[29] 
Ashkenazi, A.; Viard, M.; Unger, L.; Blumenthal, R.; Shai, Y. Sphingopeptides: Dihydrosphingosine-based fusion inhibitors against wild-type and enfuvirtide-resistant HIV-1. FASEB J.,  2012, 26(11), 4628-4636.
[http://dx.doi.org/10.1096/fj.12-215111] [PMID:  22872679] 
[30] 
Chong, H.; Wu, X.; Su, Y.; He, Y. Development of potent and long-acting HIV-1 fusion inhibitors. AIDS,  2016, 30(8), 1187-1196.
[http://dx.doi.org/10.1097/QAD.0000000000001073] [PMID:  26919736] 
[31] 
Chong, H.; Qiu, Z.; Su, Y.; Yang, L.; He, Y. Design of a highly potent HIV-1 fusion inhibitor targeting the gp41 pocket. AIDS,  2015, 29(1), 13-21.
[http://dx.doi.org/10.1097/QAD.0000000000000498] [PMID:  25562490] 
[32] 
Ding, X.; Zhang, X.; Chong, H.; Zhu, Y.; Wei, H.; Wu, X.; He, J.; Wang, X.; He, Y. Enfuvirtide (T20)-based lipopeptide is a potent hiv-1 cell fusion inhibitor: Implications for viral entry and inhibition. J. Virol.,  2017, 91(18), e00831-e17.
[http://dx.doi.org/10.1128/JVI.00831-17] [PMID:  28659478] 
[33] 
Chong, H.; Zhu, Y.; Yu, D.; He, Y. Structural and functional characterization of membrane fusion inhibitors with extremely potent activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and simian immunodeficiency virus. J. Virol.,  2018, 92(20), e01088-e18.
[http://dx.doi.org/10.1128/JVI.01088-18] [PMID:  30089693] 
[34] 
Zhu, Y.; Chong, H.; Yu, D.; Guo, Y.; Zhou, Y.; He, Y. Design and characterization of cholesterylated peptide HIV-1/2 fusion inhibitors with extremely potent and long-lasting antiviral activity. J. Virol.,  2019, 93(11), e02312-e02318.
[http://dx.doi.org/10.1128/JVI.02312-18] [PMID:  30867304] 
[35] 
Lu, M.; Blacklow, S.C.; Kim, P.S. A trimeric structural domain of the HIV-1 transmembrane glycoprotein. Nat. Struct. Biol.,  1995, 2(12), 1075-1082.
[http://dx.doi.org/10.1038/nsb1295-1075] [PMID:  8846219] 
[36] 
Debnath, A.K.; Radigan, L.; Jiang, S. Structure-based identification of small molecule antiviral compounds targeted to the gp41 core structure of the human immunodeficiency virus type 1. J. Med. Chem.,  1999, 42(17), 3203-3209.
[http://dx.doi.org/10.1021/jm990154t] [PMID:  10464007] 
[37] 
Wang, H.; Qi, Z.; Guo, A.; Mao, Q.; Lu, H.; An, X.; Xia, C.; Li, X.; Debnath, A.K.; Wu, S.; Liu, S.; Jiang, S. ADS-J1 inhibits human immunodeficiency virus type 1 entry by interacting with the gp41 pocket region and blocking fusion-active gp41 core formation. Antimicrob. Agents Chemother.,  2009, 53(12), 4987-4998.
[http://dx.doi.org/10.1128/AAC.00670-09] [PMID:  19786602] 
[38] 
Yu, F.; Lu, L.; Liu, Q.; Yu, X.; Wang, L.; He, E.; Zou, P.; Du, L.; Sanders, R.W.; Liu, S.; Jiang, S. ADS-J1 inhibits HIV-1 infection and membrane fusion by targeting the highly conserved pocket in the gp41 NHR-trimer. Biochim. Biophys. Acta,  2014, 1838(5), 1296-1305.
[http://dx.doi.org/10.1016/j.bbamem.2013.12.022] [PMID:  24388952] 
[39] 
Armand-Ugón, M.; Clotet-Codina, I.; Tintori, C.; Manetti, F.; Clotet, B.; Botta, M.; Esté, J.A. The anti-HIV activity of ADS-J1 targets the HIV-1 gp120. Virology,  2005, 343(1), 141-149.
[http://dx.doi.org/10.1016/j.virol.2005.08.007] [PMID:  16168454] 
[40] 
González-Ortega, E.; Mena, M.P.; Permanyer, M.; Ballana, E.; Clotet, B.; Esté, J.A. ADS-J1 inhibits HIV-1 entry by interacting with gp120 and does not block fusion-active gp41 core formation. Antimicrob. Agents Chemother.,  2010, 54(10), 4487-4492.
[http://dx.doi.org/10.1128/AAC.00359-10] [PMID:  20643898] 
[41] 
Liu, K.; Lu, H.; Hou, L.; Qi, Z.; Teixeira, C.; Barbault, F.; Fan, B.T.; Liu, S.; Jiang, S.; Xie, L. Design, synthesis, and biological evaluation of N-carboxyphenylpyrrole derivatives as potent HIV fusion inhibitors targeting gp41. J. Med. Chem.,  2008, 51(24), 7843-7854.
[http://dx.doi.org/10.1021/jm800869t] [PMID:  19053778] 
[42] 
Wang, Y.; Lu, H.; Zhu, Q.; Jiang, S.; Liao, Y. Structure-based design, synthesis and biological evaluation of new N-carboxyphenylpyrrole derivatives as HIV fusion inhibitors targeting gp41. Bioorg. Med. Chem. Lett.,  2010, 20(1), 189-192.
[http://dx.doi.org/10.1016/j.bmcl.2009.10.139] [PMID:  19932616] 
[43] 
Katritzky, A.R.; Tala, S.R.; Lu, H.; Vakulenko, A.V.; Chen, Q.Y.; Sivapackiam, J.; Pandya, K.; Jiang, S.; Debnath, A.K. Design, synthesis, and structure-activity relationship of a novel series of 2-aryl 5-(4-oxo-3-phenethyl-2-thioxothiazolidinylidenemethyl)furans as HIV-1 entry inhibitors. J. Med. Chem.,  2009, 52(23), 7631-7639.
[http://dx.doi.org/10.1021/jm900450n] [PMID:  19746983] 
[44] 
Frey, G.; Rits-Volloch, S.; Zhang, X.Q.; Schooley, R.T.; Chen, B.; Harrison, S.C. Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion. Proc. Natl. Acad. Sci. USA,  2006, 103(38), 13938-13943.
[http://dx.doi.org/10.1073/pnas.0601036103] [PMID:  16963566] 
[45] 
Yu, F.; Lu, L.; Du, L.; Zhu, X.; Debnath, A.K.; Jiang, S. Approaches for identification of HIV-1 entry inhibitors targeting gp41 pocket. Viruses,  2013, 5(1), 127-149.
[http://dx.doi.org/10.3390/v5010127] [PMID:  23344560] 
[46] 
Li, W.; Moore, M.J.; Vasilieva, N.; Sui, J.; Wong, S.K.; Berne, M.A.; Somasundaran, M.; Sullivan, J.L.; Luzuriaga, K.; Greenough, T.C.; Choe, H.; Farzan, M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature,  2003, 426(6965), 450-454.
[http://dx.doi.org/10.1038/nature02145] [PMID:  14647384] 
[47] 
Simmons, G.; Gosalia, D.N.; Rennekamp, A.J.; Reeves, J.D.; Diamond, S.L.; Bates, P. Inhibitors of cathepsin L prevent severe acute respiratory syndrome coronavirus entry. Proc. Natl. Acad. Sci. USA,  2005, 102(33), 11876-11881.
[http://dx.doi.org/10.1073/pnas.0505577102] [PMID:  16081529] 
[48] 
Zhu, J.; Xiao, G.; Xu, Y.; Yuan, F.; Zheng, C.; Liu, Y.; Yan, H.; Cole, D.K.; Bell, J.I.; Rao, Z.; Tien, P.; Gao, G.F. Following the rule: Formation of the 6-helix bundle of the fusion core from severe acute respiratory syndrome coronavirus spike protein and identification of potent peptide inhibitors. Biochem. Biophys. Res. Commun.,  2004, 319(1), 283-288.
[http://dx.doi.org/10.1016/j.bbrc.2004.04.141] [PMID:  15158473] 
[49] 
Liu, S.; Xiao, G.; Chen, Y.; He, Y.; Niu, J.; Escalante, C.R.; Xiong, H.; Farmar, J.; Debnath, A.K.; Tien, P.; Jiang, S. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: Implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet,  2004, 363(9413), 938-947.
[http://dx.doi.org/10.1016/S0140-6736(04)15788-7] [PMID:  15043961] 
[50] 
Bosch, B.J.; Martina, B.E.; Van Der Zee, R.; Lepault, J.; Haijema, B.J.; Versluis, C.; Heck, A.J.; De Groot, R.; Osterhaus, A.D.; Rottier, P.J. Severe acute respiratory syndrome coronavirus (SARS-CoV) infection inhibition using spike protein heptad repeat-derived peptides. Proc. Natl. Acad. Sci. USA,  2004, 101(22), 8455-8460.
[http://dx.doi.org/10.1073/pnas.0400576101] [PMID:  15150417] 
[51] 
Yuan, K.; Yi, L.; Chen, J.; Qu, X.; Qing, T.; Rao, X.; Jiang, P.; Hu, J.; Xiong, Z.; Nie, Y.; Shi, X.; Wang, W.; Ling, C.; Yin, X.; Fan, K.; Lai, L.; Ding, M.; Deng, H. Suppression of SARS-CoV entry by peptides corresponding to heptad regions on spike glycoprotein. Biochem. Biophys. Res. Commun.,  2004, 319(3), 746-752.
[http://dx.doi.org/10.1016/j.bbrc.2004.05.046] [PMID:  15184046] 
[52] 
Chu, L.H.; Chan, S.H.; Tsai, S.N.; Wang, Y.; Cheng, C.H.; Wong, K.B.; Waye, M.M.; Ngai, S.M. Fusion core structure of the severe acute respiratory syndrome coronavirus (SARS-CoV): In search of potent SARS-CoV entry inhibitors. J. Cell. Biochem.,  2008, 104(6), 2335-2347.
[http://dx.doi.org/10.1002/jcb.21790] [PMID:  18442051] 
[53] 
Liu, I.J.; Kao, C.L.; Hsieh, S.C.; Wey, M.T.; Kan, L.S.; Wang, W.K. Identification of a minimal peptide derived from heptad repeat (HR) 2 of spike protein of SARS-CoV and combination of HR1-derived peptides as fusion inhibitors. Antiviral Res.,  2009, 81(1), 82-87.
[http://dx.doi.org/10.1016/j.antiviral.2008.10.001] [PMID:  18983873] 
[54] 
Xia, S.; Liu, M.; Wang, C.; Xu, W.; Lan, Q.; Feng, S.; Qi, F.; Bao, L.; Du, L.; Liu, S.; Qin, C.; Sun, F.; Shi, Z.; Zhu, Y.; Jiang, S.; Lu, L. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res.,  2020, 30(4), 343-355.
[http://dx.doi.org/10.1038/s41422-020-0305-x] [PMID:  32231345] 
[55] 
Zhu, Y.; Yu, D.; Yan, H.; Chong, H.; He, Y. Design of potent membrane fusion inhibitors against sars-cov-2, an emerging coronavirus with high fusogenic activity. J. Virol.,  2020, 94(14), e00635-e20.
[http://dx.doi.org/10.1128/JVI.00635-20] [PMID:  32376627] 
[56] 
Lu, L.; Liu, Q.; Zhu, Y.; Chan, K.H.; Qin, L.; Li, Y.; Wang, Q.; Chan, J.F.; Du, L.; Yu, F.; Ma, C.; Ye, S.; Yuen, K.Y.; Zhang, R.; Jiang, S. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. Nat. Commun.,  2014, 5, 3067.
[http://dx.doi.org/10.1038/ncomms4067] [PMID:  24473083] 
[57] 
Wang, C.; Xia, S.; Zhang, P.; Zhang, T.; Wang, W.; Tian, Y.; Meng, G.; Jiang, S.; Liu, K. Discovery of hydrocarbon-stapled short α-helical peptides as promising middle east respiratory syndrome coronavirus (mers-cov) fusion inhibitors. J. Med. Chem.,  2018, 61(5), 2018-2026.
[http://dx.doi.org/10.1021/acs.jmedchem.7b01732] [PMID:  29442512] 
[58] 
Channappanavar, R.; Lu, L.; Xia, S.; Du, L.; Meyerholz, D.K.; Perlman, S.; Jiang, S. Protective effect of intranasal regimens containing peptidic middle east respiratory syndrome coronavirus fusion inhibitor against mers-cov infection. J. Infect. Dis.,  2015, 212(12), 1894-1903.
[http://dx.doi.org/10.1093/infdis/jiv325] [PMID:  26164863] 
[59] 
Wang, C.; Zhao, L.; Xia, S.; Zhang, T.; Cao, R.; Liang, G.; Li, Y.; Meng, G.; Wang, W.; Shi, W.; Zhong, W.; Jiang, S.; Liu, K. De novo design of α-helical lipopeptides targeting viral fusion proteins: A promising strategy for relatively broad-spectrum antiviral drug discovery. J. Med. Chem.,  2018, 61(19), 8734-8745.
[http://dx.doi.org/10.1021/acs.jmedchem.8b00890] [PMID:  30192544] 
[60] 
Xia, S.; Lan, Q.; Pu, J.; Wang, C.; Liu, Z.; Xu, W.; Wang, Q.; Liu, H.; Jiang, S.; Lu, L. Potent mers-cov fusion inhibitory peptides identified from hr2 domain in spike protein of bat coronavirus HKU4. Viruses,  2019, 11(1)E56
[http://dx.doi.org/10.3390/v11010056] [PMID:  30646495] 
[61] 
Sun, Y.; Zhang, H.; Shi, J.; Zhang, Z.; Gong, R. Identification of a novel inhibitor against middle east respiratory syndrome coronavirus. Viruses,  2017, 9(9)E255
[http://dx.doi.org/10.3390/v9090255] [PMID:  28906430] 
[62] 
Ni, L.; Zhu, J.; Zhang, J.; Yan, M.; Gao, G.F.; Tien, P. Design of recombinant protein-based SARS-CoV entry inhibitors targeting the heptad-repeat regions of the spike protein S2 domain. Biochem. Biophys. Res. Commun.,  2005, 330(1), 39-45.
[http://dx.doi.org/10.1016/j.bbrc.2005.02.117] [PMID:  15781229] 
[63] 
Kandeel, M.; Yamamoto, M.; Al-Taher, A.; Watanabe, A.; Oh-Hashi, K.; Park, B.K.; Kwon, H.J.; Inoue, J.I.; Al-Nazawi, M. Small molecule inhibitors of middle east respiratory syndrome coronavirus fusion by targeting cavities on heptad repeat trimers. Biomol. Ther. (Seoul),  2020, 28(4), 311-319.
[http://dx.doi.org/10.4062/biomolther.2019.202] [PMID:  32126736] 
[64] 
Zhao, G.; Du, L.; Ma, C.; Li, Y.; Li, L.; Poon, V.K.; Wang, L.; Yu, F.; Zheng, B.J.; Jiang, S.; Zhou, Y. A safe and convenient pseudovirus-based inhibition assay to detect neutralizing antibodies and screen for viral entry inhibitors against the novel human coronavirus MERS-CoV. Virol. J.,  2013, 10, 266.
[http://dx.doi.org/10.1186/1743-422X-10-266] [PMID:  23978242] 
[65] 
Zhou, P.; Yang, X.L.; Wang, X.G.; Hu, B.; Zhang, L.; Zhang, W.; Si, H.R.; Zhu, Y.; Li, B.; Huang, C.L.; Chen, H.D.; Chen, J.; Luo, Y.; Guo, H.; Jiang, R.D.; Liu, M.Q.; Chen, Y.; Shen, X.R.; Wang, X.; Zheng, X.S.; Zhao, K.; Chen, Q.J.; Deng, F.; Liu, L.L.; Yan, B.; Zhan, F.X.; Wang, Y.Y.; Xiao, G.F.; Shi, Z.L. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature,  2020, 579(7798), 270-273.
[http://dx.doi.org/10.1038/s41586-020-2012-7] [PMID:  32015507] 
[66] 
Hoffmann, M.; Kleine-Weber, H.; Schroeder, S.; Krüger, N.; Herrler, T.; Erichsen, S.; Schiergens, T.S.; Herrler, G.; Wu, N.H.; Nitsche, A.; Müller, M.A.; Drosten, C.; Pöhlmann, S. SARS-CoV-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor. Cell,  2020, 181(2), 271-280.e8.
[http://dx.doi.org/10.1016/j.cell.2020.02.052] [PMID:  32142651] 
[67] 
Xia, S.; Lan, Q.; Su, S.; Wang, X.; Xu, W.; Liu, Z.; Zhu, Y.; Wang, Q.; Lu, L.; Jiang, S. The role of furin cleavage site in SARS-CoV-2 spike protein-mediated membrane fusion in the presence or absence of trypsin. Signal Transduct. Target. Ther.,  2020, 5(1), 92.
[http://dx.doi.org/10.1038/s41392-020-0184-0] [PMID:  32532959] 
[68] 
Thoennes, S.; Li, Z.N.; Lee, B.J.; Langley, W.A.; Skehel, J.J.; Russell, R.J.; Steinhauer, D.A. Analysis of residues near the fusion peptide in the influenza hemagglutinin structure for roles in triggering membrane fusion. Virology,  2008, 370(2), 403-414.
[http://dx.doi.org/10.1016/j.virol.2007.08.035] [PMID:  17936324] 
[69] 
Hamilton, B.S.; Whittaker, G.R.; Daniel, S. Influenza virus-mediated membrane fusion: Determinants of hemagglutinin fusogenic activity and experimental approaches for assessing virus fusion. Viruses,  2012, 4(7), 1144-1168.
[http://dx.doi.org/10.3390/v4071144] [PMID:  22852045] 
[70] 
Park, H.E.; Gruenke, J.A.; White, J.M. Leash in the groove mechanism of membrane fusion. Nat. Struct. Biol.,  2003, 10(12), 1048-1053.
[http://dx.doi.org/10.1038/nsb1012] [PMID:  14595397] 
[71] 
Lee, K.K.; Pessi, A.; Gui, L.; Santoprete, A.; Talekar, A.; Moscona, A.; Porotto, M. Capturing a fusion intermediate of influenza hemagglutinin with a cholesterol-conjugated peptide, a new antiviral strategy for influenza virus. J. Biol. Chem.,  2011, 286(49), 42141-42149.
[http://dx.doi.org/10.1074/jbc.M111.254243] [PMID:  21994935] 
[72] 
Bodian, D.L.; Yamasaki, R.B.; Buswell, R.L.; Stearns, J.F.; White, J.M.; Kuntz, I.D. Inhibition of the fusion-inducing conformational change of influenza hemagglutinin by benzoquinones and hydroquinones. Biochemistry,  1993, 32(12), 2967-2978.
[http://dx.doi.org/10.1021/bi00063a007] [PMID:  8457561] 
[73] 
Russell, R.J.; Kerry, P.S.; Stevens, D.J.; Steinhauer, D.A.; Martin, S.R.; Gamblin, S.J.; Skehel, J.J. Structure of influenza hemagglutinin in complex with an inhibitor of membrane fusion. Proc. Natl. Acad. Sci. USA,  2008, 105(46), 17736-17741.
[http://dx.doi.org/10.1073/pnas.0807142105] [PMID:  19004788] 
[74] 
Vanderlinden, E.; Göktas, F.; Cesur, Z.; Froeyen, M.; Reed, M.L.; Russell, C.J.; Cesur, N.; Naesens, L. Novel inhibitors of influenza virus fusion: Structure-activity relationship and interaction with the viral hemagglutinin. J. Virol.,  2010, 84(9), 4277-4288.
[http://dx.doi.org/10.1128/JVI.02325-09] [PMID:  20181685] 
[75] 
Yu, M.; Si, L.; Wang, Y.; Wu, Y.; Yu, F.; Jiao, P.; Shi, Y.; Wang, H.; Xiao, S.; Fu, G.; Tian, K.; Wang, Y.; Guo, Z.; Ye, X.; Zhang, L.; Zhou, D. Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J. Med. Chem.,  2014, 57(23), 10058-10071.
[http://dx.doi.org/10.1021/jm5014067] [PMID:  25383779] 
[76] 
Si, L.; Meng, K.; Tian, Z.; Sun, J.; Li, H.; Zhang, Z.; Soloveva, V.; Li, H.; Fu, G.; Xia, Q.; Xiao, S.; Zhang, L.; Zhou, D. Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes. Sci. Adv.,  2018, 4(11)eaau8408
[http://dx.doi.org/10.1126/sciadv.aau8408] [PMID:  30474060] 
[77] 
Lou, Z.; Xu, Y.; Xiang, K.; Su, N.; Qin, L.; Li, X.; Gao, G.F.; Bartlam, M.; Rao, Z. Crystal structures of Nipah and Hendra virus fusion core proteins. FEBS J.,  2006, 273(19), 4538-4547.
[http://dx.doi.org/10.1111/j.1742-4658.2006.05459.x] [PMID:  16972940] 
[78] 
Zhao, X.; Singh, M.; Malashkevich, V.N.; Kim, P.S. Structural characterization of the human respiratory syncytial virus fusion protein core. Proc. Natl. Acad. Sci. USA,  2000, 97(26), 14172-14177.
[http://dx.doi.org/10.1073/pnas.260499197] [PMID:  11106388] 
[79] 
Wang, L.F.; Yu, M.; Hansson, E.; Pritchard, L.I.; Shiell, B.; Michalski, W.P.; Eaton, B.T. The exceptionally large genome of Hendra virus: Support for creation of a new genus within the family Paramyxoviridae. J. Virol.,  2000, 74(21), 9972-9979.
[http://dx.doi.org/10.1128/JVI.74.21.9972-9979.2000] [PMID:  11024125] 
[80] 
Xu, Y.; Gao, S.; Cole, D.K.; Zhu, J.; Su, N.; Wang, H.; Gao, G.F.; Rao, Z. Basis for fusion inhibition by peptides: Analysis of the heptad repeat regions of the fusion proteins from Nipah and Hendra viruses, newly emergent zoonotic paramyxoviruses. Biochem. Biophys. Res. Commun.,  2004, 315(3), 664-670.
[http://dx.doi.org/10.1016/j.bbrc.2004.01.115] [PMID:  14975752] 
[81] 
Xu, Y.; Lou, Z.; Liu, Y.; Cole, D.K.; Su, N.; Qin, L.; Li, X.; Bai, Z.; Rao, Z.; Gao, G.F. Crystallization and preliminary crystallographic analysis of the fusion core from two new zoonotic paramyxoviruses, Nipah virus and Hendra virus. Acta Crystallogr. D Biol. Crystallogr.,  2004, 60(Pt 6), 1161-1164.
[http://dx.doi.org/10.1107/S0907444904009515] [PMID:  15159588] 
[82] 
Wang, L.; Harcourt, B.H.; Yu, M.; Tamin, A.; Rota, P.A.; Bellini, W.J.; Eaton, B.T. Molecular biology of Hendra and Nipah viruses. Microbes Infect.,  2001, 3(4), 279-287.
[http://dx.doi.org/10.1016/S1286-4579(01)01381-8] [PMID:  11334745] 
[83] 
Harcourt, B.H.; Tamin, A.; Ksiazek, T.G.; Rollin, P.E.; Anderson, L.J.; Bellini, W.J.; Rota, P.A. Molecular characterization of Nipah virus, a newly emergent paramyxovirus. Virology,  2000, 271(2), 334-349.
[http://dx.doi.org/10.1006/viro.2000.0340] [PMID:  10860887] 
[84] 
Bossart, K.N.; Wang, L.F.; Eaton, B.T.; Broder, C.C. Functional expression and membrane fusion tropism of the envelope glycoproteins of Hendra virus. Virology,  2001, 290(1), 121-135.
[http://dx.doi.org/10.1006/viro.2001.1158] [PMID:  11882997] 
[85] 
Bossart, K.N.; Mungall, B.A.; Crameri, G.; Wang, L.F.; Eaton, B.T.; Broder, C.C. Inhibition of Henipavirus fusion and infection by heptad-derived peptides of the Nipah virus fusion glycoprotein. Virol. J.,  2005, 2, 57.
[http://dx.doi.org/10.1186/1743-422X-2-57] [PMID:  16026621] 
[86] 
Porotto, M.; Doctor, L.; Carta, P.; Fornabaio, M.; Greengard, O.; Kellogg, G.E.; Moscona, A. Inhibition of hendra virus fusion. J. Virol.,  2006, 80(19), 9837-9849.
[http://dx.doi.org/10.1128/JVI.00736-06] [PMID:  16973588] 
[87] 
Porotto, M.; Carta, P.; Deng, Y.; Kellogg, G.E.; Whitt, M.; Lu, M.; Mungall, B.A.; Moscona, A. Molecular determinants of antiviral potency of paramyxovirus entry inhibitors. J. Virol.,  2007, 81(19), 10567-10574.
[http://dx.doi.org/10.1128/JVI.01181-07] [PMID:  17652384] 
[88] 
Porotto, M.; Yokoyama, C.C.; Palermo, L.M.; Mungall, B.; Aljofan, M.; Cortese, R.; Pessi, A.; Moscona, A. Viral entry inhibitors targeted to the membrane site of action. J. Virol.,  2010, 84(13), 6760-6768.
[http://dx.doi.org/10.1128/JVI.00135-10] [PMID:  20357085] 
[89] 
Pessi, A.; Langella, A.; Capitò, E.; Ghezzi, S.; Vicenzi, E.; Poli, G.; Ketas, T.; Mathieu, C.; Cortese, R.; Horvat, B.; Moscona, A.; Porotto, M. A general strategy to endow natural fusion-protein-derived peptides with potent antiviral activity. PLoS One,  2012, 7(5)e36833
[http://dx.doi.org/10.1371/journal.pone.0036833] [PMID:  22666328] 
[90] 
Mathieu, C.; Augusto, M.T.; Niewiesk, S.; Horvat, B.; Palermo, L.M.; Sanna, G.; Madeddu, S.; Huey, D.; Castanho, M.A.; Porotto, M.; Santos, N.C.; Moscona, A. Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides. Sci. Rep.,  2017, 7, 43610.
[http://dx.doi.org/10.1038/srep43610] [PMID:  28344321] 
[91] 
Porotto, M.; Rockx, B.; Yokoyama, C.C.; Talekar, A.; Devito, I.; Palermo, L.M.; Liu, J.; Cortese, R.; Lu, M.; Feldmann, H.; Pessi, A.; Moscona, A. Inhibition of Nipah virus infection in vivo: Targeting an early stage of paramyxovirus fusion activation during viral entry. PLoS Pathog.,  2010, 6(10)e1001168
[http://dx.doi.org/10.1371/journal.ppat.1001168] [PMID:  21060819] 
[92] 
Mathieu, C.; Porotto, M.; Figueira, T.N.; Horvat, B.; Moscona, A. Fusion inhibitory lipopeptides engineered for prophylaxis of nipah virus in primates. J. Infect. Dis.,  2018, 218(2), 218-227.
[http://dx.doi.org/10.1093/infdis/jiy152] [PMID:  29566184] 
[93] 
Lambert, D.M.; Barney, S.; Lambert, A.L.; Guthrie, K.; Medinas, R.; Davis, D.E.; Bucy, T.; Erickson, J.; Merutka, G.; Petteway, S.R. Jr. Peptides from conserved regions of paramyxovirus fusion (F) proteins are potent inhibitors of viral fusion. Proc. Natl. Acad. Sci. USA,  1996, 93(5), 2186-2191.
[http://dx.doi.org/10.1073/pnas.93.5.2186] [PMID:  8700906] 
[94] 
Outlaw, V.K.; Bottom-Tanzer, S.; Kreitler, D.F.; Gellman, S.H.; Porotto, M.; Moscona, A. Dual inhibition of human parainfluenza type 3 and respiratory syncytial virus infectivity with a single agent. J. Am. Chem. Soc.,  2019, 141(32), 12648-12656.
[http://dx.doi.org/10.1021/jacs.9b04615] [PMID:  31268705] 
[95] 
Niedermeier, S.; Singethan, K.; Rohrer, S.G.; Matz, M.; Kossner, M.; Diederich, S.; Maisner, A.; Schmitz, J.; Hiltensperger, G.; Baumann, K.; Holzgrabe, U.; Schneider-Schaulies, J. A small-molecule inhibitor of Nipah virus envelope protein-mediated membrane fusion. J. Med. Chem.,  2009, 52(14), 4257-4265.
[http://dx.doi.org/10.1021/jm900411s] [PMID:  19499921] 
[96] 
Magro, M.; Andreu, D.; Gómez-Puertas, P.; Melero, J.A.; Palomo, C. Neutralization of human respiratory syncytial virus infectivity by antibodies and low-molecular-weight compounds targeted against the fusion glycoprotein. J. Virol.,  2010, 84(16), 7970-7982.
[http://dx.doi.org/10.1128/JVI.00447-10] [PMID:  20534864] 
[97] 
Wang, E.; Sun, X.; Qian, Y.; Zhao, L.; Tien, P.; Gao, G.F. Both heptad repeats of human respiratory syncytial virus fusion protein are potent inhibitors of viral fusion. Biochem. Biophys. Res. Commun.,  2003, 302(3), 469-475.
[http://dx.doi.org/10.1016/S0006-291X(03)00197-9] [PMID:  12615056] 
[98] 
Root, M.J.; Kay, M.S.; Kim, P.S. Protein design of an HIV-1 entry inhibitor. Science,  2001, 291(5505), 884-888.
[http://dx.doi.org/10.1126/science.1057453] [PMID:  11229405] 
[99] 
Park, M.; Matsuura, H.; Lamb, R.A.; Barron, A.E.; Jardetzky, T.S. A fluorescence polarization assay using an engineered human respiratory syncytial virus F protein as a direct screening platform. Anal. Biochem.,  2011, 409(2), 195-201.
[http://dx.doi.org/10.1016/j.ab.2010.10.020] [PMID:  20971054] 
[100] 
Ni, L.; Zhao, L.; Qian, Y.; Zhu, J.; Jin, Z.; Chen, Y.W.; Tien, P.; Gao, G.F. Design and characterization of human respiratory syncytial virus entry inhibitors. Antivir. Ther.,  2005, 10(7), 833-840.
[PMID:  16312179] 
[101] 
McKimm-Breschkin, J. VP-14637 ViroPharma. Curr. Opin. Investig. Drugs,  2000, 1(4), 425-427.
[PMID:  11249694] 
[102] 
Douglas, J.L.; Panis, M.L.; Ho, E.; Lin, K.Y.; Krawczyk, S.H.; Grant, D.M.; Cai, R.; Swaminathan, S.; Cihlar, T. Inhibition of respiratory syncytial virus fusion by the small molecule VP-14637 via specific interactions with F protein. J. Virol.,  2003, 77(9), 5054-5064.
[http://dx.doi.org/10.1128/JVI.77.9.5054-5064.2003] [PMID:  12692208] 
[103] 
Andries, K.; Moeremans, M.; Gevers, T.; Willebrords, R.; Sommen, C.; Lacrampe, J.; Janssens, F.; Wyde, P.R. Substituted benzimidazoles with nanomolar activity against respiratory syncytial virus. Antiviral Res.,  2003, 60(3), 209-219.
[http://dx.doi.org/10.1016/j.antiviral.2003.07.004] [PMID:  14638397] 
[104] 
Douglas, J.L.; Panis, M.L.; Ho, E.; Lin, K.Y.; Krawczyk, S.H.; Grant, D.M.; Cai, R.; Swaminathan, S.; Chen, X.; Cihlar, T. Small molecules VP-14637 and JNJ-2408068 inhibit respiratory syncytial virus fusion by similar mechanisms. Antimicrob. Agents Chemother.,  2005, 49(6), 2460-2466.
[http://dx.doi.org/10.1128/AAC.49.6.2460-2466.2005] [PMID:  15917547] 
[105] 
Bonfanti, J.F.; Meyer, C.; Doublet, F.; Fortin, J.; Muller, P.; Queguiner, L.; Gevers, T.; Janssens, P.; Szel, H.; Willebrords, R.; Timmerman, P.; Wuyts, K.; van Remoortere, P.; Janssens, F.; Wigerinck, P.; Andries, K. Selection of a respiratory syncytial virus fusion inhibitor clinical candidate. 2. Discovery of a morpholinopropylaminobenzimidazole derivative (TMC353121). J. Med. Chem.,  2008, 51(4), 875-896.
[http://dx.doi.org/10.1021/jm701284j] [PMID:  18254606] 
[106] 
Roymans, D.; De Bondt, H.L.; Arnoult, E.; Geluykens, P.; Gevers, T.; Van Ginderen, M.; Verheyen, N.; Kim, H.; Willebrords, R.; Bonfanti, J.F.; Bruinzeel, W.; Cummings, M.D.; van Vlijmen, H.; Andries, K. Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein. Proc. Natl. Acad. Sci. USA,  2010, 107(1), 308-313.
[http://dx.doi.org/10.1073/pnas.0910108106] [PMID:  19966279] 
[107] 
Cianci, C.; Yu, K.L.; Combrink, K.; Sin, N.; Pearce, B.; Wang, A.; Civiello, R.; Voss, S.; Luo, G.; Kadow, K.; Genovesi, E.V.; Venables, B.; Gulgeze, H.; Trehan, A.; James, J.; Lamb, L.; Medina, I.; Roach, J.; Yang, Z.; Zadjura, L.; Colonno, R.; Clark, J.; Meanwell, N.; Krystal, M. Orally active fusion inhibitor of respiratory syncytial virus. Antimicrob. Agents Chemother.,  2004, 48(2), 413-422.
[http://dx.doi.org/10.1128/AAC.48.2.413-422.2004] [PMID:  14742189] 
[108] 
Cianci, C.; Genovesi, E.V.; Lamb, L.; Medina, I.; Yang, Z.; Zadjura, L.; Yang, H.; D’Arienzo, C.; Sin, N.; Yu, K.L.; Combrink, K.; Li, Z.; Colonno, R.; Meanwell, N.; Clark, J.; Krystal, M. Oral efficacy of a respiratory syncytial virus inhibitor in rodent models of infection. Antimicrob. Agents Chemother.,  2004, 48(7), 2448-2454.
[http://dx.doi.org/10.1128/AAC.48.7.2448-2454.2004] [PMID:  15215093] 
[109] 
Cianci, C.; Langley, D.R.; Dischino, D.D.; Sun, Y.; Yu, K.L.; Stanley, A.; Roach, J.; Li, Z.; Dalterio, R.; Colonno, R.; Meanwell, N.A.; Krystal, M. Targeting a binding pocket within the trimer-of-hairpins: Small-molecule inhibition of viral fusion. Proc. Natl. Acad. Sci. USA,  2004, 101(42), 15046-15051.
[http://dx.doi.org/10.1073/pnas.0406696101] [PMID:  15469910] 
[110] 
Mackman, R.L.; Sangi, M.; Sperandio, D.; Parrish, J.P.; Eisenberg, E.; Perron, M.; Hui, H.; Zhang, L.; Siegel, D.; Yang, H.; Saunders, O.; Boojamra, C.; Lee, G.; Samuel, D.; Babaoglu, K.; Carey, A.; Gilbert, B.E.; Piedra, P.A.; Strickley, R.; Iwata, Q.; Hayes, J.; Stray, K.; Kinkade, A.; Theodore, D.; Jordan, R.; Desai, M.; Cihlar, T. Discovery of an oral respiratory syncytial virus (RSV) fusion inhibitor (GS-5806) and clinical proof of concept in a human RSV challenge study. J. Med. Chem.,  2015, 58(4), 1630-1643.
[http://dx.doi.org/10.1021/jm5017768] [PMID:  25574686] 
[111] 
Perron, M.; Stray, K.; Kinkade, A.; Theodore, D.; Lee, G.; Eisenberg, E.; Sangi, M.; Gilbert, B.E.; Jordan, R.; Piedra, P.A.; Toms, G.L.; Mackman, R.; Cihlar, T. GS-5806 inhibits a broad range of respiratory syncytial virus clinical isolates by blocking the virus-cell fusion process. Antimicrob. Agents Chemother.,  2015, 60(3), 1264-1273.
[http://dx.doi.org/10.1128/AAC.01497-15] [PMID:  26666922] 
[112] 
Roymans, D.; Alnajjar, S.S.; Battles, M.B.; Sitthicharoenchai, P.; Furmanova-Hollenstein, P.; Rigaux, P.; Berg, J.V.D.; Kwanten, L.; Ginderen, M.V.; Verheyen, N.; Vranckx, L.; Jaensch, S.; Arnoult, E.; Voorzaat, R.; Gallup, J.M.; Larios-Mora, A.; Crabbe, M.; Huntjens, D.; Raboisson, P.; Langedijk, J.P.; Ackermann, M.R.; McLellan, J.S.; Vendeville, S.; Koul, A. Therapeutic efficacy of a respiratory syncytial virus fusion inhibitor. Nat. Commun.,  2017, 8(1), 167.
[http://dx.doi.org/10.1038/s41467-017-00170-x] [PMID:  28761099] 
[113] 
Zheng, X.; Liang, C.; Wang, L.; Wang, B.; Liu, Y.; Feng, S.; Wu, J.Z.; Gao, L.; Feng, L.; Chen, L.; Guo, T.; Shen, H.C.; Yun, H. Discovery of benzoazepinequinoline (BAQ) derivatives as novel, potent, orally bioavailable respiratory syncytial virus fusion inhibitors. J. Med. Chem.,  2018, 61(22), 10228-10241.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01394] [PMID:  30339388] 
[114] 
Zheng, X.; Gao, L.; Wang, L.; Liang, C.; Wang, B.; Liu, Y.; Feng, S.; Zhang, B.; Zhou, M.; Yu, X.; Xiang, K.; Chen, L.; Guo, T.; Shen, H.C.; Zou, G.; Wu, J.Z.; Yun, H. Discovery of ziresovir as a potent, selective, and orally bioavailable respiratory syncytial virus fusion protein Inhibitor. J. Med. Chem.,  2019, 62(13), 6003-6014.
[http://dx.doi.org/10.1021/acs.jmedchem.9b00654] [PMID:  31194544] 
[115] 
Moller-Tank, S.; Maury, W. Ebola virus entry: A curious and complex series of events. PLoS Pathog.,  2015, 11(4)e1004731
[http://dx.doi.org/10.1371/journal.ppat.1004731] [PMID:  25928849] 
[116] 
Saeed, M.F.; Kolokoltsov, A.A.; Albrecht, T.; Davey, R.A. Cellular entry of ebola virus involves uptake by a macropinocytosis-like mechanism and subsequent trafficking through early and late endosomes. PLoS Pathog.,  2010, 6(9)e1001110
[http://dx.doi.org/10.1371/journal.ppat.1001110] [PMID:  20862315] 
[117] 
Nanbo, A.; Imai, M.; Watanabe, S.; Noda, T.; Takahashi, K.; Neumann, G.; Halfmann, P.; Kawaoka, Y. Ebolavirus is internalized into host cells via macropinocytosis in a viral glycoprotein-dependent manner. PLoS Pathog.,  2010, 6(9)e1001121
[http://dx.doi.org/10.1371/journal.ppat.1001121] [PMID:  20886108] 
[118] 
Aleksandrowicz, P.; Marzi, A.; Biedenkopf, N.; Beimforde, N.; Becker, S.; Hoenen, T.; Feldmann, H.; Schnittler, H. J. Ebola virus enters host cells by macropinocytosis and clathrin- mediated endocytosis. J Infect Dis, 2011, 204(Suppl 3 (Suppl 3)), S957-S967.
[http://dx.doi.org/10.1093/infdis/jir326] 
[119] 
Carette, J.E.; Raaben, M.; Wong, A.C.; Herbert, A.S.; Obernosterer, G.; Mulherkar, N.; Kuehne, A.I.; Kranzusch, P.J.; Griffin, A.M.; Ruthel, G.; Dal Cin, P.; Dye, J.M.; Whelan, S.P.; Chandran, K.; Brummelkamp, T.R. Ebola virus entry requires the cholesterol transporter Niemann-Pick C1. Nature,  2011, 477(7364), 340-343.
[http://dx.doi.org/10.1038/nature10348] [PMID:  21866103] 
[120] 
Weissenhorn, W.; Carfí, A.; Lee, K.H.; Skehel, J.J.; Wiley, D.C. Crystal structure of the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain. Mol. Cell,  1998, 2(5), 605-616.
[http://dx.doi.org/10.1016/S1097-2765(00)80159-8] [PMID:  9844633] 
[121] 
Malashkevich, V.N.; Schneider, B.J.; McNally, M.L.; Milhollen, M.A.; Pang, J.X.; Kim, P.S. Core structure of the envelope glycoprotein GP2 from Ebola virus at 1.9-A resolution. Proc. Natl. Acad. Sci. USA,  1999, 96(6), 2662-2667.
[http://dx.doi.org/10.1073/pnas.96.6.2662] [PMID:  10077567] 
[122] 
Watanabe, S.; Takada, A.; Watanabe, T.; Ito, H.; Kida, H.; Kawaoka, Y. Functional importance of the coiled-coil of the Ebola virus glycoprotein. J. Virol.,  2000, 74(21), 10194-10201.
[http://dx.doi.org/10.1128/JVI.74.21.10194-10201.2000] [PMID:  11024148] 
[123] 
Netter, R.C.; Amberg, S.M.; Balliet, J.W.; Biscone, M.J.; Vermeulen, A.; Earp, L.J.; White, J.M.; Bates, P. Heptad repeat 2-based peptides inhibit avian sarcoma and leukosis virus subgroup a infection and identify a fusion intermediate. J. Virol.,  2004, 78(24), 13430-13439.
[http://dx.doi.org/10.1128/JVI.78.24.13430-13439.2004] [PMID:  15564453] 
[124] 
Chandran, K.; Sullivan, N.J.; Felbor, U.; Whelan, S.P.; Cunningham, J.M. Endosomal proteolysis of the Ebola virus glycoprotein is necessary for infection. Science,  2005, 308(5728), 1643-1645.
[http://dx.doi.org/10.1126/science.1110656] [PMID:  15831716] 
[125] 
Higgins, C.D.; Koellhoffer, J.F.; Chandran, K.; Lai, J.R. C-peptide inhibitors of Ebola virus glycoprotein-mediated cell entry: Effects of conjugation to cholesterol and side chain-side chain crosslinking. Bioorg. Med. Chem. Lett.,  2013, 23(19), 5356-5360.
[http://dx.doi.org/10.1016/j.bmcl.2013.07.056] [PMID:  23962564] 
Cite As
Current Medicinal Chemistry

Viral Entry Inhibitors Targeting Six-Helical Bundle Core against Highly Pathogenic Enveloped Viruses with Class I Fusion Proteins

Abstract
