Enveloped virus entry as a pharmacological target: viral membrane fusion machineries and their inhibitors

Cover Page

Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription Access

Abstract

Enveloped virus entry into the host cell mediated by the viral fusion glycoproteins represents an earliest step in viral infection, the inhibition of which offers a number of advantages over the antivirals with other mechanisms of action. Viral glycoproteins are classified into three classes with rather different structures, but, despite that, they share some functional features, such as the separation of receptor recognition/binding function and membrane fusion function into two different subunits or domains. All of them are transmembrane proteins anchored in the virion`s membrane, and possessing a hydrophobic structure (fusion peptide or fusion loop), which is inserted in target cell membrane early in fusion. Here, we describe the membrane fusion machinery of all 3 classes of viral glycoproteins and indicate their domains and structures, which can serve as the targets for entry inhibitors with different mechanisms of action. The examples of large and small molecule entry inhbitiors belonging to the groups of affinity blockers, inhibitors of glycoprotein-receptor binding, fusion inhibitors, anchor inhibitors and compounds blocking the function of membrane-proximal external region (MPER) of viral glycoproteins are provided. Finally, the perspectives of developing broadly acting entry inhibitors are discussed.

About the authors

S. V. Cheresiz

Zelmanʹs Institute of Medicine and Psychology, Novosibirsk State University

Email: cheresiz@yandex.ru
Novosibirsk, 630090 Russia

E. A. Ulyanova

Zelmanʹs Institute of Medicine and Psychology, Novosibirsk State University

Novosibirsk, 630090 Russia

A. G. Pokrovsky

Zelmanʹs Institute of Medicine and Psychology, Novosibirsk State University

Novosibirsk, 630090 Russia

References

  1. Dimitrov D.S. (2004) Virus entry: molecular mechanisms and biomedical applications. Nat. Rev. Microbiol. 2(2), 109–122. https://doi.org/10.1038/nrmicro817
  2. Melby T., Westby M. (2009) Inhibitors of viral entry. Handb. Exp. Pharmacol. 189, 177–202. https://doi.org/10.1007/978-3-540-79086-0_7
  3. Eggink D., Bontjer I., de Taeye S.W., Langedijk J.P.M., Berkhout B., Sanders R.W. (2019) HIV-1 anchor inhibitors and membrane fusion inhibitors target distinct but overlapping steps in virus entry. J. Biol. Chem. 294(15), 5736–5746. https://doi.org/10.1074/jbc.RA119.007360
  4. Groß R., Dias Loiola L.M., Issmail L., Uhlig N., Eberlein V., Conzelmann C., Olari L.R., Rauch L., Lawrenz J., Weil T., Müller J.A., Cardoso M.B., Gilg A., Larsson O., Höglund U., Pålsson S.A., Tvilum A.S., Løvschall K.B., Kristensen M.M., Spetz A.L., Hontonnou F., Galloux M., Grunwald T., Zelikin A.N., Münch J. (2022) Macromolecular viral entry inhibitors as broad-spectrum first-line antivirals with activity against SARS-CoV-2. Adv. Sci. (Weinh). 9(20), e2201378. https://doi.org/10.1002/advs.202201378
  5. Gaucherand L., Gaglia M.M. (2022) The role of viral RNA degrading factors in shutoff of host gene expression. Annu. Rev. Virol. 9(1), 213–238. https://doi.org/10.1146/annurev-virology-100120-012345
  6. Du S., Liu X., Cai Q. (2018) Viral-mediated mRNA degradation for pathogenesis. Biomedicines. 6(4), 111. https://doi.org/10.3390/biomedicines6040111
  7. Moore J.P., Doms R.W. (2003) The entry of entry inhibitors: a fusion of science and medicine. Proc. Natl. Acad. Sci. USA. 100(19), 10598–10602. https://doi.org/10.1073/pnas.1932511100
  8. Lazzarin A. (2005) Enfuvirtide: the first HIV fusion inhibitor. Expert Opin. Pharmacother. 6(3), 453–464. https://doi.org/10.1517/14656566.6.3.453
  9. Dorr P., Westby M., Dobbs S., Griffin P., Irvine B., Macartney M., Mori J., Rickett G., Smith-Burchnell C., Napier C., Webster R., Armour D., Price D., Stammen B., Wood A., Perros M. (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob. Agents Chemother. 49(11), 4721–4732. https://doi.org/10.1128/AAC.49.11.4721-4732.2005
  10. Woollard S.M., Kanmogne G.D. (2015) Maraviroc: a review of its use in HIV infection and beyond. Drug. Des. Devel. Ther. 9, 5447–5468. https://doi.org/10.2147/DDDT.S90580
  11. Su S., Xu W., Jiang S. (2022) Virus entry inhibitors: past, present, and future. In: Virus Entry Inhibitors. Advances in Experimental Medicine and Biology. Eds Jiang S., Lu L. Singapore: Springer, V. 1366, p. 1–11. https://doi.org/10.1007/978-981-16-8702-0_1
  12. Silva-Júnior E.F.D. (2022) Entry Inhibitors of RNA viruses. Curr. Med. Chem. 29(4), 609–611. https://doi.org/10.2174/092986732904220207113503
  13. Rey F.A., Lok S.M. (2018) Common features of enveloped viruses and implications for immunogen design for next-generation vaccines. Cell. 172(6), 1319–1334. https://doi.org/10.1016/j.cell.2018.02.054
  14. Maginnis M.S. (2023) β-arrestins and G protein-coupled receptor kinases in viral entry: a graphical review. Cell Signal. 102, 110558. https://doi.org/10.1016/j.cellsig.2022.110558
  15. Riedel C., Vasishtan D., Siebert C.A., Whittle C., Lehmann M.J., Mothes W., Grünewald K. (2017) Native structure of a retroviral envelope protein and its conformational change upon interaction with the target cell. J. Struct. Biol. 197(2), 172–180. https://doi.org/10.1016/j.jsb.2016.06.017
  16. Herold N., Anders-Ößwein M., Glass B., Eckhardt M., Müller B., Kräusslich H.G. (2014) HIV-1 entry in SupT1-R5, CEM-ss, and primary CD4+ T cells occurs at the plasma membrane and does not require endocytosis. J. Virol. 88(24), 13956–13970. https://doi.org/10.1128/JVI.01543-14
  17. Daecke J., Fackler O.T., Dittmar M.T., Kräusslich H.G. (2005) Involvement of clathrin-mediated endocytosis in human immunodeficiency virus type 1 entry. J. Virol. 79(3), 1581–1594. https://doi.org/10.1128/JVI.79.3.1581-1594.2005
  18. Van Wilgenburg B., Moore M.D., James W.S., Cowley S.A. (2014) The productive entry pathway of HIV-1 in macrophages is dependent on endocytosis through lipid rafts containing CD4. PLoS One. 9(1), e86071. https://doi.org/10.1371/journal.pone.0086071
  19. Chauhan A., Mehla R., Vijayakumar T.S., Handy I. (2014) Endocytosis-mediated HIV-1 entry and its significance in the elusive behavior of the virus in astrocytes. Virology. 456‒457, 1–19. https://doi.org/10.1016/j.virol.2014.03.002
  20. Kalia M., Jameel S. (2011) Virus entry paradigms. Amino Acids. 41(5), 1147–1157. https://doi.org/10.1007/s00726-009-0363-3
  21. Schornberg K., Matsuyama S., Kabsch K., Delos S., Bouton A., White J. (2006) Role of endosomal cathepsins in entry mediated by the Ebola virus glycoprotein. J. Virol. 80(8), 4174–4178. https://doi.org/10.1128/JVI.80.8.4174-4178.2006
  22. Hunt C.L., Lennemann N.J., Maury W. (2012) Filovirus entry: a novelty in the viral fusion world. Viruses. 4(2), 258–275. https://doi.org/10.3390/v4020258
  23. Schowalter R.M., Chang A., Robach J.G., Buchholz U.J., Dutch R.E. (2009) Low-pH triggering of human metapneumovirus fusion: essential residues and importance in entry. J. Virol. 83(3), 1511–1522. https://doi.org/10.1128/JVI.01381-08
  24. Kinder J.T., Klimyte E.M., Chang A., Williams J.V., Dutch R.E. (2019) Human metapneumovirus fusion protein triggering: Increasing complexities by analysis of new HMPV fusion proteins. Virology. 531, 248–254. https://doi.org/10.1016/j.virol.2019.03.003
  25. Mothes W., Boerger A.L., Narayan S., Cunningham J.M., Young J.A. (2000) Retroviral entry mediated by receptor priming and low pH triggering of an envelope glycoprotein. Cell. 103(4), 679–689. https://doi.org/10.1016/s0092-8674(00)00170-7
  26. Plemper R.K. (2011) Cell entry of enveloped viruses. Curr. Opin. Virol. 1(2), 92–100. https://doi.org/10.1016/j.coviro.2011.06.002
  27. Ghietto L.M., Gil P.I., Olmos Quinteros P., Gomez E., Piris F.M., Kunda P., Contigiani M., Paglini M.G. (2022) Members of Venezuelan Equine Encephalitis complex entry into host cells by clathrin-mediated endocytosis in a pH-dependent manner. Sci. Rep. 12(1), 14556. https://doi.org/10.1038/s41598-022-18846-w
  28. Yang F., Lin S., Ye F., Yang J., Qi J., Chen Z., Lin X., Wang J., Yue D., Cheng Y., Chen Z., Chen H., You Y., Zhang Z., Yang Y., Yang M., Sun H., Li Y., Cao Y., Yang S., Wei Y., Gao G.F., Lu G. (2020) Structural analysis of rabies virus glycoprotein reveals pH-dependent conformational changes and interactions with a neutralizing antibody. Cell Host Microbe. 27(3), 441–453.e7. https://doi.org/10.1016/j.chom.2019.12.012
  29. Nikolic J., Belot L., Raux H., Legrand P., Gaudin Y., Albertini A. (2018) Structural basis for the recognition of LDL-receptor family members by VSV glycoprotein. Nat. Commun. 9(1), 1029. https://doi.org/10.1038/s41467-018-03432-4
  30. Rutten L., Gilman M.S.A., Blokland S., Juraszek J., McLellan J.S., Langedijk J.P.M. (2020) Structure-based design of prefusion-stabilized filovirus glycoprotein trimers. Cell Rep. 30(13), 4540–4550.e3. https://doi.org/10.1016/j.celrep.2020.03.025
  31. Bohan D., Ert H.V., Ruggio N., Rogers K.J., Badreddine M., Aguilar Briseño J.A., Rojas Chavez R.A, Gao B., Stokowy T., Christakou E., Micklem D., Gausdal G., Haim H., Minna J., Lorens J.B., Maury W. (2021) Phosphatidylserine receptors enhance SARS-CoV-2 infection: AXL as a therapeutic target for COVID-19. bioRxiv. 2021.06.15.448419. https://doi.org/10.1101/2021.06.15.448419
  32. Uzunova K., Filipova E., Pavlova V., Vekov T. (2020) Insights into antiviral mechanisms of remdesivir, lopinavir/ritonavir and chloroquine/hydroxychloroquine affecting the new SARS-CoV-2. Biomed. Pharmacother. 131, 110668. https://doi.org/10.1016/j.biopha.2020.110668
  33. Devaux C.A., Rolain J.M., Colson P., Raoult D. (2020) New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int. J. Antimicrob. Agents. 55(5), 105938. https://doi.org/10.1016/j.ijantimicag.2020.105938
  34. Cox R.M., Plemper R.K. (2017) Structure and organization of paramyxovirus particles. Curr. Opin. Virol. 24, 105–114. https://doi.org/10.1016/j.coviro.2017.05.004
  35. Schibli D.J., Weissenhorn W. (2004) Class I and class II viral fusion protein structures reveal similar principles in membrane fusion. Mol. Membr. Biol. 21(6), 361–371. https://doi.org/10.1080/09687860400017784
  36. Fu Q., Shaik M.M., Cai Y., Ghantous F., Piai A., Peng H., Rits-Volloch S., Liu Z., Harrison S.C., Seaman M.S., Chen B., Chou J.J. (2018) Structure of the membrane proximal external region of HIV-1 envelope glycoprotein. Proc. Natl. Acad. Sci. USA. 115(38), E8892–E8899. https://doi.org/10.1073/pnas.1807259115
  37. Guardado-Calvo P., Rey F.A. (2021) The viral class ii membrane fusion machinery: divergent evolution from an ancestral heterodimer. Viruses. 13(12), 2368. https://doi.org/10.3390/v13122368
  38. Roman-Sosa G., Kielian M. (2011) The interaction of alphavirus E1 protein with exogenous domain III defines stages in virus-membrane fusion. J. Virol. 85(23), 12271–12279. https://doi.org/10.1128/JVI.05902–11
  39. Kielian M. (2006) Class II virus membrane fusion proteins. Virology. 344(1), 38–47. https://doi.org/10.1016/j.virol.2005.09.036
  40. Lu L., Su S., Yang H., Jiang S. (2021) Antivirals with common targets against highly pathogenic viruses. Cell. 184(6), 1604–1620. https://doi.org/10.1016/j.cell.2021.02.013
  41. de Wispelaere M., Lian W., Potisopon S., Li P.C., Jang J., Ficarro S.B., Clark M.J., Zhu X., Kaplan J.B., Pitts J.D., Wales T.E., Wang J., Engen J.R., Marto J.A., Gray N.S., Yang P.L. (2018) Inhibition of flaviviruses by targeting a conserved pocket on the viral envelope protein. Cell Chem. Biol. 25(8), 1006–1016. e8. https://doi.org/10.1016/j.chembiol.2018.05.011
  42. Schmidt A.G., Yang P.L., Harrison S.C. (2010) Peptide inhibitors of dengue-virus entry target a late-stage fusion intermediate. PLoS Pathog. 6(4), e1000851. https://doi.org/10.1371/journal.ppat.1000851
  43. Yu Y., Deng Y.Q., Zou P., Wang Q., Dai Y., Yu F., Du L., Zhang N.N., Tian M., Hao J.N., Meng Y., Li Y., Zhou X., Fuk-Woo Chan J., Yuen K.Y., Qin C.F., Jiang S., Lu L. (2017) A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses. Nat. Commun. 8, 15672. https://doi.org/10.1038/ncomms15672
  44. Rangel M.V., Catanzaro N., Thannickal S.A., Crotty K.A., Noval M.G., Johnson K.E.E., Ghedin E., Lazear H.M., Stapleford K.A. (2022) Structurally conserved domains between Flavivirus and Alphavirus fusion glycoproteins contribute to replication and infectious-virion production. J. Virol. 96(2), e0177421. https://doi.org/10.1128/JVI.01774-21
  45. Regan A.D., Whittaker G.R. (2013) Entry of rhabdoviruses into animal cells. Adv. Exp. Med. Biol. 790, 167–177. https://doi.org/10.1007/978-1-4614-7651-1_9
  46. Beilstein F., Abou Hamdan A., Raux H., Belot L., Ouldali M., Albertini A.A., Gaudin Y. (2020) Identification of a pH-Sensitive Switch in VSV-G and a crystal structure of the G pre-fusion state highlight the VSV-G structural transition pathway. Cell Rep. 32(7), 108042. https://doi.org/10.1016/j.celrep.2020.108042
  47. Connolly S.A., Jardetzky T.S., Longnecker R. (2021) The structural basis of herpesvirus entry. Nat. Rev. Microbiol. 19(2), 110–121. https://doi.org/10.1038/s41579-020-00448-w
  48. Cooper R.S., Georgieva E.R., Borbat P.P., Freed J.H., Heldwein E.E. (2018) Structural basis for membrane anchoring and fusion regulation of the herpes simplex virus fusogen gB. Nat. Struct. Mol. Biol. 25, 416–424. https://doi.org/10.1038/s41594-018-0060-6
  49. Mazzon M., Marsh M. (2019) Targeting viral entry as a strategy for broad-spectrum antivirals. F1000Res. 8, F1000 Faculty Rev-1628. https://doi.org/10.12688/f1000research.19694.1
  50. Conzelmann C., Müller J.A., Perkhofer L., Sparrer K.M., Zelikin A.N., Münch J., Kleger A. (2020) Inhaled and systemic heparin as a repurposed direct antiviral drug for prevention and treatment of COVID-19. Clin. Med. (Lond). 20(6), e218–e221. https://doi.org/10.7861/clinmed.2020-0351
  51. Mycroft-West C.J., Su D., Pagani I., Rudd T.R., Elli S., Gandhi N.S., Guimond S.E., Miller G.J., Meneghetti M.C.Z., Nader H.B., Li Y., Nunes Q.M., Procter P., Mancini N., Clementi M., Bisio A., Forsyth N.R., Ferro V., Turnbull J.E., Guerrini M., Fernig D.G., Vicenzi E., Yates E.A., Lima M.A., Skidmore M.A. (2020) Heparin inhibits cellular invasion by SARS-CoV-2: structural dependence of the interaction of the spike S1 receptor-binding domain with heparin. Thromb. Haemost. 120(12), 1700–1715. https://doi.org/10.1055/s-0040-1721319
  52. Dey P., Bergmann T., Cuellar-Camacho J.L., Ehrmann S., Chowdhury M.S., Zhang M., Azab W. (2018) Multivalent flexible nanogels exhibit broad-spectrum antiviral activity by blocking virus entry. ACS Nano. 12(7), 6429–6442. https://doi.org/10.1021/acsnano.8b01616
  53. Dogra P., Martin E.B., Williams A., Richardson R.L., Foster J.S., Hackenback N., Kennel S.J., Sparer T.E., Wall J.S. (2015) Novel heparan sulfate-binding peptides for blocking herpesvirus entry. PLoS One. 10(5), e0126239. https://doi.org/10.1371/journal.pone.0126239
  54. Sachdev D.D., Zerhouni-Layachi B., Ortigoza M., Profy A.T., Tuen M., Hioe C.E., Klotman M.E. (2009) The differential binding and activity of PRO 2000 against diverse HIV-1 envelopes. J. Acquir. Immune Defic. Syndr. 51(2), 125–129. https://doi.org/10.1097/qai.0b013e31819f9e31
  55. Vanderlinden E., Boonen A., Noppen S., Schoofs G., Imbrechts M., Geukens N., Snoeck R, Stevaert A., Naesens L., Andrei G., Schols D. (2023) PRO-2000 exhibits SARS-CoV-2 antiviral activity by interfering with spike-heparin binding. Antiviral. Res. 217, 105700. https://doi.org/10.1016/j.antiviral.2023.105700
  56. Eaton E.F., Hoesley C.J. (2014) Barrier methods for human immunodeficiency virus prevention. Infect. Dis. Clin. North Am. 28(4), 585–599. https://doi.org/10.1016/j.idc.2014.08.006
  57. Chhabra M., Ferro V. (2020) PI-88 and related heparan sulfate mimetics. Adv. Exp. Med. Biol. 1221, 473–491. https://doi.org/10.1007/978-3-030-34521-1_19
  58. Maginnis M.S. (2018) Virus-receptor interactions: the key to cellular invasion. J. Mol. Biol. 430(17), 2590–2611. https://doi.org/10.1016/j.jmb.2018.06.024
  59. Sriwilaijaroen N., Suzuki Y. (2022) Roles of sialyl glycans in HCoV-OC43, HCoV-HKU1, MERS-CoV and SARS-CoV-2 infections. Methods Mol. Biol. 2556, 243–271. https://doi.org/10.1007/978-1-0716-2635-1_17
  60. Bai Y., Jones J.C., Wong S.S., Zanin M. (2021) Antivirals targeting the surface glycoproteins of influenza virus: mechanisms of action and resistance. Viruses. 13(4), 624. https://doi.org/10.3390/v13040624
  61. Bhatia S., Lauster D., Bardua M., Ludwig K., Angioletti-Uberti S., Popp N., Hoffmann U., Paulus F., Budt M., Stadtmüller M., Wolff T., Hamann A., Böttcher C., Herrmann A., Haag R. (2017) Linear polysialoside outperforms dendritic analogs for inhibition of influenza virus infection in vitro and in vivo. Biomaterials. 138, 22–34. https://doi.org/10.1016/j.biomaterials.2017.05.028
  62. Bohan D., Maury W. (2021) Enveloped RNA virus utilization of phosphatidylserine receptors: advantages of exploiting a conserved, widely available mechanism of entry. PLoS Pathog. 17(9), e1009899. https://doi.org/10.1371/journal.ppat.1009899
  63. Wang Y., Zhou Z., Wu X., Li T., Wu J., Cai M., Nie J., Wang W., Cui Z. (2023) Pseudotyped viruses. Adv. Exp. Med. Biol. 1407, 1–27. https://doi.org/10.1007/978-981-99-0113-5_1
  64. Kononova A.A., Sokolova A.S., Cheresiz S.V., Yarovaya O.I., Nikitina R.A., Chepurnov A.A., Pokrovsky A.G., Salakhutdinov N.F. (2017) N-Heterocyclic borneol derivatives as inhibitors of Marburg virus glycoprotein-mediated VSIV pseudotype entry. Medchemcomm. 8(12), 2233–2237. https://doi.org/10.1039/c7md00424a
  65. Cheresiz S.V., Kononona A.A., Skarnovich M., Volkova A.N., Poletaeva Yu. A., Emaminia F., Pyankov O.V., Schultz E.E., Pokrovsky A.G. (2022) An amide derivative of betulonic acid as a new inhibitor of Sars-CoV-2 spike protein-mediated cell entry and Sars-CoV-2 infection. Insights Chem. Biochem. 2(2), 1‒11. ICBC. MS.ID.000535. https://doi.org/10.33552/ICBC.2022.02.000535
  66. De Clercq E. (2015) AMD3100/CXCR4 inhibitor. Front. Immunol. 6, 276. https://doi.org/10.3389/fimmu.2015.00276
  67. Ferain T., Hoveyda H., Ooms F., Schols D., Bernard J., Fraser G. (2011) Agonist-induced internalization of CC chemokine receptor 5 as a mechanism to inhibit HIV replication. J. Pharmacol. Exp. Ther. 337(3), 655–662. https://doi.org/10.1124/jpet.111.179622
  68. Muccini C., Canetti D., Castagna A., Spagnuolo V. (2022) Efficacy and safety profile of fostemsavir for the treatment of people with human immunodeficiency virus-1 (HIV-1): current evidence and place in therapy. Drug Des. Devel. Ther. 16, 297–304. https://doi.org/10.2147/DDDT.S273660
  69. Wild C., Greenwell T., Matthews T. (1993) A synthetic peptide from HIV-1 gp41 is a potent inhibitor of virus-mediated cell-cell fusion. AIDS Res. Hum. Retroviruses. 9(11), 1051–1053. https://doi.org/10.1089/aid.1993.9.1051
  70. Berkhout B., Eggink D., Sanders R.W. (2012) Is there a future for antiviral fusion inhibitors? Curr. Opin. Virol. 2(1), 50–59. https://doi.org/10.1016/j.coviro.2012.01.002
  71. Yao Q., Compans R.W. (1996) Peptides corresponding to the heptad repeat sequence of human parainfluenza virus fusion protein are potent inhibitors of virus infection. Virology. 223(1), 103–112. https://doi.org/10.1006/viro.1996.0459
  72. Khetawat D., Broder C.C. (2010) A functional henipavirus envelope glycoprotein pseudotyped lentivirus assay system. Virol. J. 7, 312. https://doi.org/10.1186/1743-422X-7-312
  73. Mathieu C., Huey D., Jurgens E., Welsch J.C., DeVito I., Talekar A., Horvat B., Niewiesk S., Moscona A., Porotto M. (2015) Prevention of measles virus infection by intranasal delivery of fusion inhibitor peptides. J. Virol. 89(2), 1143–1155. https://doi.org/10.1128/JVI.02417-14
  74. Higgins C.D., Koellhoffer J.F., Chandran K., Lai J.R. (2013) 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. 23(19), 5356–5360. https://doi.org/10.1016/j.bmcl.2013.07.056
  75. Gaillard V., Galloux M., Garcin D., Eléouët J.F., Le Goffic R., Larcher T., Rameix-Welti M.A., Boukadiri A., Héritier J., Segura J.M., Baechler E., Arrell M., Mottet-Osman G., Nyanguile O. (2017) A short double-stapled peptide inhibits respiratory syncytial virus entry and spreading. Antimicrob. Agents Chemother. 61(4), e02241–16. https://doi.org/10.1128/AAC.02241+16
  76. Liu I.J., Kao C.L., Hsieh S.C., Wey M.T., Kan L.S., Wang W.K. (2009) 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. 81(1), 82–87. https://doi.org/10.1016/j.antiviral.2008.10.001
  77. Panchal D., Kataria J., Patel K., Crowe K., Pai V., Azizogli A.R., Kadian N., Sanyal S., Roy A., Dodd-O J., Acevedo-Jake A.M., Kumar V.A. (2021) Peptide-based inhibitors for SARS-CoV-2 and SARS-CoV. Adv. Ther. (Weinh). 4(10), 2100104. https://doi.org/10.1002/adtp.202100104
  78. Channappanavar R., Lu L., Xia S., Du L., Meyerholz D.K., Perlman S., Jiang S. (2015) Protective effect of intranasal regimens containing peptidic middle east respiratory syndrome coronavirus fusion inhibitor against MERS-CoV infection. J. Infect. Dis. 212(12), 1894–1903. https://doi.org/10.1093/infdis/jiv325
  79. Zhao P., Wang B., Ji C.M., Cong X., Wang M., Huang Y.W. (2018) Identification of a peptide derived from the heptad repeat 2 region of the porcine epidemic diarrhea virus (PEDV) spike glycoprotein that is capable of suppressing PEDV entry and inducing neutralizing antibodies. Antiviral. Res. 150, 1–8. https://doi.org/10.1016/j.antiviral.2017.11.021
  80. Mizukoshi F., Baba K., Goto Y., Setoguchi A., Fujino Y., Ohno K., Oishi S., Kodera Y., Fujii N., Tsujimoto H. (2009) Antiviral activity of membrane fusion inhibitors that target gp40 of the feline immunodeficiency virus envelope protein. Vet. Microbiol. 136(1–2), 155–159. https://doi.org/10.1016/j.vetmic.2008.10.009
  81. Zhang Q., Liang T., Nandakumar K.S., Liu S. (2021) Emerging and state of the art hemagglutinin-targeted influenza virus inhibitors. Expert Opin. Pharmacother. 22(6), 715–728. https://doi.org/10.1080/14656566.2020.1856814
  82. Wang W., Cole A.M., Hong T., Waring A.J., Lehrer R.I. (2003) Retrocyclin, an antiretroviral theta-defensin, is a lectin. J. Immunol. 170(9), 4708–4716. https://doi.org/10.4049/jimmunol.170.9.4708
  83. Kudryashova E., Zani A., Vilmen G., Sharma A., Lu W., Yount J.S., Kudryashov D.S. (2022) Inhibition of SARS-CoV-2 infection by human defensin HNP1 and retrocyclin RC-101. J. Mol. Biol. 434(6), 167225. https://doi.org/10.1016/j.jmb.2021.167225
  84. Ahmadi K., Farasat A., Rostamian M., Johari B., Madanchi H. (2022) Enfuvirtide, an HIV-1 fusion inhibitor peptide, can act as a potent SARS-CoV-2 fusion inhibitor: an in silico drug repurposing study. J. Biomol. Struct. Dyn. 40(12), 5566–5576. https://doi.org/10.1080/07391102.2021
  85. Marqus S., Pirogova E., Piva T.J. (2017) Evaluation of the use of therapeutic peptides for cancer treatment. J. Biomed. Sci. 24(1), 21. https://doi.org/10.1186/s12929-017-0328-x
  86. Mayaux J.F., Bousseau A., Pauwels R., Huet T., Hénin Y., Dereu N., Evers M., Soler F., Poujade C., De Clercq E. (1994) Triterpene derivatives that block entry of human immunodeficiency virus type 1 into cells. Proc. Natl. Acad. Sci. USA. 91(9), 3564–3568. https://doi.org/10.1073/pnas.91.9.3564
  87. Jiang S., Lu H., Liu S., Zhao Q., He Y., Debnath A.K. (2004) 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. 48(11), 4349–4359. https://doi.org/10.1128/AAC.48.11.4349-4359.2004
  88. Frey G., Rits-Volloch S., Zhang X.Q., Schooley R.T., Chen B., Harrison S.C. (2006) Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion. Proc. Natl. Acad. Sci. USA. 103(38), 13938–13943. https://doi.org/10.1073/pnas.060103610
  89. Cai L., Gochin M. (2007) A novel fluorescence intensity screening assay identifies new low-molecular-weight inhibitors of the gp41 coiled-coil domain of human immunodeficiency virus type 1. Antimicrob. Agents Chemother. 51(7), 2388‒2395. https://doi.org/10.1128/AAC.00150-07
  90. Jiang X., Jia Q., Lu L., Yu F., Zheng J., Shi W., Cai L., Jiang S., Liu K. (2016) A novel bispecific peptide HIV-1 fusion inhibitor targeting the N-terminal heptad repeat and fusion peptide domains in gp41. Amino Acids. 48(12), 2867–2873. https://doi.org/10.1007/s00726-016-2325-x
  91. Herrera E., Gomara M.J., Mazzini S., Ragg E., Haro I. (2009) Synthetic peptides of hepatitis G virus (GBV-C/HGV) in the selection of putative peptide inhibitors of the HIV-1 fusion peptide. J. Phys. Chem. B. 113(20), 7383–7391. https://doi.org/10.1021/jp900707t
  92. Murray E.J., Leaman D.P., Pawa N., Perkins H., Pickford C., Perros M., Zwick M.B., Butler S.L. (2010) A low-molecular-weight entry inhibitor of both CCR5- and CXCR4-tropic strains of human immunodeficiency virus type 1 targets a novel site on gp41. J. Virol. 84(14), 7288–7299. https://doi.org/10.1128/JVI.00535-10
  93. Zhao P., Wang B., Ji C.M., Cong X., Wang M., Huang Y.W. (2018) Identification of a peptide derived from the heptad repeat 2 region of the porcine epidemic diarrhea virus (PEDV) spike glycoprotein that is capable of suppressing PEDV entry and inducing neutralizing antibodies. Antiviral. Res. 150, 1–8. https://doi.org/10.1016/j.antiviral.2017.11.021
  94. Ozorowski G., Torres J.L., Santos-Martins D., Forli S., Ward A.B. (2020) A strain-specific inhibitor of receptor-bound HIV-1 targets a pocket near the fusion peptide. Cell Rep. 33(8), 108428. https://doi.org/10.1016/j.celrep.2020.108428
  95. Lee J., Nyenhuis D.A., Nelson E.A., Cafiso D.S., White J.M., Tamm L.K. (2017) Structure of the Ebola virus envelope protein MPER/TM domain and its interaction with the fusion loop explains their fusion activity. Proc. Natl. Acad. Sci. USA. 114(38), E7987–E7996. https://doi.org/10.1073/pnas.1708052114
  96. Grimaldi M., Stillitano I., Amodio G., Santoro A., Buonocore M., Moltedo O., Remondelli P., D’Ursi A.M. (2018) Structural basis of antiviral activity of peptides from MPER of FIV gp36. PLoS One. 13(9), e0204042. https://doi.org/10.1371/journal.pone.0204042
  97. Xiao T., Frey G., Fu Q., Lavine C.L., Scott D.A., Seaman M.S., Chou J.J., Chen B. (2020) HIV-1 fusion inhibitors targeting the membrane-proximal external region of Env spikes. Nat. Chem. Biol. 16(5), 529–537. https://doi.org/10.1038/s41589-020-0496-y
  98. Koehler J.W., Smith J.M., Ripoll D.R., Spik K.W., Taylor S.L., Badger C.V., Grant R.J., Ogg M.M., Wallqvist A., Guttieri M.C., Garry R.F., Schmaljohn C.S. (2013) A fusion-inhibiting peptide against Rift Valley fever virus inhibits multiple, diverse viruses. PLoS Negl. Trop. Dis. 7(9), e2430. https://doi.org/10.1371/journal.pntd.0002430
  99. Gaffney A., Nangarlia A., Ang C.G., Gossert S., Rashad Ahmed A.A., Hossain M.A., Abrams C.F., Smith A.B. 3rd, Chaiken I. (2021) HIV-1 Env-dependent cell killing by bifunctional small-molecule/peptide conjugates. ACS Chem. Biol. 16(1), 193–204. https://doi.org/10.1021/acschembio.0c00888
  100. Ang C.G., Carter E., Haftl A., Zhang S., Rashad A.A., Kutzler M., Abrams C.F., Chaiken I.M. (2021) Peptide triazole thiol irreversibly inactivates metastable HIV-1 Env by accessing conformational triggers intrinsic to virus-cell entry. Microorganisms. 9(6), 1286. https://doi.org/10.3390/microorganisms9061286
  101. de Wispelaere M., Lian W., Potisopon S., Li P.C., Jang J., Ficarro S.B., Clark M.J., Zhu X., Kaplan J.B., Pitts J.D., Wales T.E., Wang J., Engen J.R., Marto J.A., Gray N.S., Yang P.L. (2018) Inhibition of flaviviruses by targeting a conserved pocket on the viral envelope protein. Cell Chem. Biol. 25(8), 1006–1016.e8. https://doi.org/10.1016/j.chembiol.2018.05.011
  102. Miller D.K., Lenard J. (1980) Inhibition of vesicular stomatitis virus infection by spike glycoprotein. Evidence for an intracellular, G protein-requiring step. J. Cell Biol. 84(2), 430–437. https://doi.org/10.1083/jcb.84.2.430
  103. Tsiang H., Superti F. (1984) Ammonium chloride and chloroquine inhibit rabies virus infection in neuroblastoma cells. Brief report. Arch. Virol. 81(3–4), 377–382. https://doi.org/10.1007/BF01310010
  104. Wu Y., Pons V., Noël R., Kali S., Shtanko O., Davey R.A., Popoff M.R., Tordo N., Gillet D., Cintrat J.C., Barbier J. (2019) DABMA: a derivative of ABMA with improved broad-spectrum inhibitory activity of toxins and viruses. ACS Med. Chem. Lett. 10(8), 1140–1147. https://doi.org/10.1021/acsmedchemlett.9b00155
  105. Andersen P.I., Ianevski A., Lysvand H., Vitkauskiene A., Oksenych V., Bjørås M., Telling K., Lutsar I., Dumpis U., Irie Y., Tenson T., Kantele A., Kainov D.E. (2020) Discovery and development of safe-in-man broad-spectrum antiviral agents. Int. J. Infect. Dis. 93, 268–276. https://doi.org/10.1016/j.ijid.2020.02.018
  106. Bauer D.J., Stvincent L., Kempe C.H., Downie A.W. (1963) Prophylactic treatment of small pox contacts with N-methylisatin beta-thiosemicarbazone (Compound 33t57, Marboran). Lancet. 35, 494–496.
  107. Müller B., Kräusslich H.G. (2009) Antiviral strategies. Handb. Exp. Pharmacol. 189(189), 1–24. https://doi.org/10.1007/978-3-540-79086-0_1
  108. Borysiewicz J., Lucka-Sobstel B. (1978) The effect of certain mannich N-bases, derivatives of isatin beta-thiosemicarbazone, on the replication of vaccinia virus in in vitro studies. Acta Microbiol. Pol. 27, 111–121.
  109. Ison M.G. (2017) Antiviral treatments. Clin. Chest. Med. 38(1), 139–153. https://doi.org/10.1016/j.ccm.2016.11.008
  110. Sierra-Aragón S., Walter H. (2012) Targets for inhibition of HIV replication: entry, enzyme action, release and maturation. Intervirology. 55(2), 84–97. https://doi.org/10.1159/000331995
  111. Delang L., Neyts J., Vliegen I., Abrignani S., Neddermann P., De Francesco R. (2013) Hepatitis C virus-specific directly acting antiviral drugs. Curr. Top. Microb. Immunol. 369, 289–320. https://doi.org/10.1007/978-3-642-27340-7_12
  112. Wong J.P., Christopher M.E., Salazar A.M., Sun L.Q., Viswanathan S., Wang M., Saravolac E.G., Cairns M.J. (2010) Broad-spectrum and virus-specific nucleic acid-based antivirals against influenza. Front. Biosci. (Schol Ed). 2(2), 791–800. https://doi.org/10.2741/s102
  113. Huchting J. (2020) Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections. Antivir. Chem. Chemother. 28, 2040206620976786. https://doi.org/10.1177/2040206620976786
  114. 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. (2014) Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses. J. Med. Chem. 57(23), 10058–10071. https://doi.org/10.1021/jm5014067
  115. 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. (2018) Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes. Sci. Adv. 4(11), eaau8408. https://doi.org/10.1126/sciadv.aau8408
  116. Vigant F., Santos N.C., Lee B. (2015) Broad-spectrum antivirals against viral fusion. Nat. Rev. Microbiol. 13(7), 426–437. https://doi.org/10.1038/nrmicro3475
  117. Al-Bari M.A.A. (2017) Targeting endosomal acidification by chloroquine analogs as a promising strategy for the treatment of emerging viral diseases. Pharmacol. Res. Perspect. 5(1), e00293. https://doi.org/10.1002/prp2.293
  118. Ma-Lauer Y., Lei J., Hilgenfeld R., von Brunn A. (2012) Virus-host interactomes — antiviral drug discovery. Curr. Opin. Virol. 2(5), 614–621. https://doi.org/10.1016/j.coviro.2012.09.003
  119. Zhou Y., Vedantham P., Lu K., Agudelo J., Carrion R.Jr., Nunneley J.W., Barnard D., Pöhlmann S., McKerrow J.H., Renslo A.R., Simmons G. (2015) Protease inhibitors targeting coronavirus and filovirus entry. Antiviral. Res. 116, 76–84. https://doi.org/10.1016/j.antiviral.2015.01.011
  120. Scarcella M., d’Angelo D., Ciampa M., Tafuri S., Avallone L., Pavone L.M., De Pasquale V. (2022) The key role of lysosomal protease cathepsins in viral infections. Int. J. Mol. Sci. 23(16), 9089. https://doi.org/10.3390/ijms23169089
  121. Izaguirre G. (2019) The proteolytic regulation of virus cell entry by furin and other proprotein convertases. Viruses. 11(9), 837. https://doi.org/10.3390/v11090837
  122. Mahajan S., Choudhary S., Kumar P., Tomar S. (2021) Antiviral strategies targeting host factors and mechanisms obliging +ssRNA viral pathogens. Bioorg. Med. Chem. 46, 116356. https://doi.org/10.1016/j.bmc.2021.116356
  123. Meineke R., Rimmelzwaan G.F., Elbahesh H. (2019) Influenza virus infections and cellular kinases. Viruses. 11(2), 171. https://doi.org/10.3390/v11020171
  124. Pillaiyar T., Laufer S. (2022) Kinases as potential therapeutic targets for anti-coronaviral therapy. J. Med. Chem. 65(2), 955–982. https://doi.org/10.1021/acs.jmedchem.1c00335

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2025 Russian Academy of Sciences

Согласие на обработку персональных данных с помощью сервиса «Яндекс.Метрика»

1. Я (далее – «Пользователь» или «Субъект персональных данных»), осуществляя использование сайта https://journals.rcsi.science/ (далее – «Сайт»), подтверждая свою полную дееспособность даю согласие на обработку персональных данных с использованием средств автоматизации Оператору - федеральному государственному бюджетному учреждению «Российский центр научной информации» (РЦНИ), далее – «Оператор», расположенному по адресу: 119991, г. Москва, Ленинский просп., д.32А, со следующими условиями.

2. Категории обрабатываемых данных: файлы «cookies» (куки-файлы). Файлы «cookie» – это небольшой текстовый файл, который веб-сервер может хранить в браузере Пользователя. Данные файлы веб-сервер загружает на устройство Пользователя при посещении им Сайта. При каждом следующем посещении Пользователем Сайта «cookie» файлы отправляются на Сайт Оператора. Данные файлы позволяют Сайту распознавать устройство Пользователя. Содержимое такого файла может как относиться, так и не относиться к персональным данным, в зависимости от того, содержит ли такой файл персональные данные или содержит обезличенные технические данные.

3. Цель обработки персональных данных: анализ пользовательской активности с помощью сервиса «Яндекс.Метрика».

4. Категории субъектов персональных данных: все Пользователи Сайта, которые дали согласие на обработку файлов «cookie».

5. Способы обработки: сбор, запись, систематизация, накопление, хранение, уточнение (обновление, изменение), извлечение, использование, передача (доступ, предоставление), блокирование, удаление, уничтожение персональных данных.

6. Срок обработки и хранения: до получения от Субъекта персональных данных требования о прекращении обработки/отзыва согласия.

7. Способ отзыва: заявление об отзыве в письменном виде путём его направления на адрес электронной почты Оператора: info@rcsi.science или путем письменного обращения по юридическому адресу: 119991, г. Москва, Ленинский просп., д.32А

8. Субъект персональных данных вправе запретить своему оборудованию прием этих данных или ограничить прием этих данных. При отказе от получения таких данных или при ограничении приема данных некоторые функции Сайта могут работать некорректно. Субъект персональных данных обязуется сам настроить свое оборудование таким способом, чтобы оно обеспечивало адекватный его желаниям режим работы и уровень защиты данных файлов «cookie», Оператор не предоставляет технологических и правовых консультаций на темы подобного характера.

9. Порядок уничтожения персональных данных при достижении цели их обработки или при наступлении иных законных оснований определяется Оператором в соответствии с законодательством Российской Федерации.

10. Я согласен/согласна квалифицировать в качестве своей простой электронной подписи под настоящим Согласием и под Политикой обработки персональных данных выполнение мною следующего действия на сайте: https://journals.rcsi.science/ нажатие мною на интерфейсе с текстом: «Сайт использует сервис «Яндекс.Метрика» (который использует файлы «cookie») на элемент с текстом «Принять и продолжить».