A broad-spectrum antiviral targeting entry of enveloped viruses

Mike C. Wolf, Alexander Freiberg, Tinghu Zhang, Zeynep Akyol-Ataman, Andrew Grock, Patrick W. Hong, Jianrong Li, Natalya F. Watson, Angela Q. Fang, Hector C. Aguilar, Matteo Porotto, Anna N. Honko, Robert Damoiseaux, John P. Miller, Sara E. Woodson, Steven Chantasirivisal, Vanessa Fontanes, Oscar A. Negrete, Paul Krogstad, Asim DasguptaAnne Moscona, Lisa E. Hensley, Sean P. Whelan, Kym F. Faull, Michael R. Holbrook, Michael E. Jung, Benhur Lee

Research output: Contribution to journalArticle

146 Citations (Scopus)

Abstract

We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both thepolar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studieswith lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic windowthat exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.

Original languageEnglish (US)
Pages (from-to)3157-3162
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number7
DOIs
StatePublished - Feb 16 2010

Fingerprint

Virus Internalization
Antiviral Agents
Cell Fusion
Viruses
Membranes
Rhodanine
Orthobunyavirus
Rift Valley fever virus
Arenavirus
Viral Envelope Proteins
Poxviridae
Virus Attachment
Flavivirus
Influenza A virus
Virus Diseases
Structure-Activity Relationship
Membrane Lipids
Virion
HIV-1
Lipids

Keywords

  • Fusion inhibitor
  • Lipid membrane
  • Small molecule
  • Viral entry
  • Virology

ASJC Scopus subject areas

  • General

Cite this

A broad-spectrum antiviral targeting entry of enveloped viruses. / Wolf, Mike C.; Freiberg, Alexander; Zhang, Tinghu; Akyol-Ataman, Zeynep; Grock, Andrew; Hong, Patrick W.; Li, Jianrong; Watson, Natalya F.; Fang, Angela Q.; Aguilar, Hector C.; Porotto, Matteo; Honko, Anna N.; Damoiseaux, Robert; Miller, John P.; Woodson, Sara E.; Chantasirivisal, Steven; Fontanes, Vanessa; Negrete, Oscar A.; Krogstad, Paul; Dasgupta, Asim; Moscona, Anne; Hensley, Lisa E.; Whelan, Sean P.; Faull, Kym F.; Holbrook, Michael R.; Jung, Michael E.; Lee, Benhur.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 7, 16.02.2010, p. 3157-3162.

Research output: Contribution to journalArticle

Wolf, MC, Freiberg, A, Zhang, T, Akyol-Ataman, Z, Grock, A, Hong, PW, Li, J, Watson, NF, Fang, AQ, Aguilar, HC, Porotto, M, Honko, AN, Damoiseaux, R, Miller, JP, Woodson, SE, Chantasirivisal, S, Fontanes, V, Negrete, OA, Krogstad, P, Dasgupta, A, Moscona, A, Hensley, LE, Whelan, SP, Faull, KF, Holbrook, MR, Jung, ME & Lee, B 2010, 'A broad-spectrum antiviral targeting entry of enveloped viruses', Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 7, pp. 3157-3162. https://doi.org/10.1073/pnas.0909587107
Wolf, Mike C. ; Freiberg, Alexander ; Zhang, Tinghu ; Akyol-Ataman, Zeynep ; Grock, Andrew ; Hong, Patrick W. ; Li, Jianrong ; Watson, Natalya F. ; Fang, Angela Q. ; Aguilar, Hector C. ; Porotto, Matteo ; Honko, Anna N. ; Damoiseaux, Robert ; Miller, John P. ; Woodson, Sara E. ; Chantasirivisal, Steven ; Fontanes, Vanessa ; Negrete, Oscar A. ; Krogstad, Paul ; Dasgupta, Asim ; Moscona, Anne ; Hensley, Lisa E. ; Whelan, Sean P. ; Faull, Kym F. ; Holbrook, Michael R. ; Jung, Michael E. ; Lee, Benhur. / A broad-spectrum antiviral targeting entry of enveloped viruses. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 7. pp. 3157-3162.
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AU - Freiberg, Alexander

AU - Zhang, Tinghu

AU - Akyol-Ataman, Zeynep

AU - Grock, Andrew

AU - Hong, Patrick W.

AU - Li, Jianrong

AU - Watson, Natalya F.

AU - Fang, Angela Q.

AU - Aguilar, Hector C.

AU - Porotto, Matteo

AU - Honko, Anna N.

AU - Damoiseaux, Robert

AU - Miller, John P.

AU - Woodson, Sara E.

AU - Chantasirivisal, Steven

AU - Fontanes, Vanessa

AU - Negrete, Oscar A.

AU - Krogstad, Paul

AU - Dasgupta, Asim

AU - Moscona, Anne

AU - Hensley, Lisa E.

AU - Whelan, Sean P.

AU - Faull, Kym F.

AU - Holbrook, Michael R.

AU - Jung, Michael E.

AU - Lee, Benhur

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N2 - We describe an antiviral small molecule, LJ001, effective against numerous enveloped viruses including Influenza A, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses, and HIV-1. In sharp contrast, the compound had no effect on the infection of nonenveloped viruses. In vitro and in vivo assays showed no overt toxicity. LJ001 specifically intercalated into viral membranes, irreversibly inactivated virions while leaving functionally intact envelope proteins, and inhibited viral entry at a step after virus binding but before virus-cell fusion. LJ001 pretreatment also prevented virus-induced mortality from Ebola and Rift Valley fever viruses. Structure-activity relationship analyses of LJ001, a rhodanine derivative, implicated both thepolar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus-cell but not cell-cell fusion, and further studieswith lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic windowthat exists between static viral membranes and biogenic cellular membranes with reparative capacity. In sum, our data reveal a class of broad-spectrum antivirals effective against enveloped viruses that target the viral lipid membrane and compromises its ability to mediate virus-cell fusion.

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KW - Small molecule

KW - Viral entry

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