Giuseppe
Emeritus
A broad-spectrum antiviral targeting entry of enveloped viruses (Proc Natl Acad Sci USA, abstract, edited)
A broad-spectrum antiviral targeting entry of enveloped viruses
1. Mike C. Wolf a, 2. Alexander N. Freiberg b,1, 3. Tinghu Zhang c,1, 4. Zeynep Akyol-Ataman a,1, 5. Andrew Grock a, 6. Patrick W. Hong a, 7. Jianrong Li d,2, 8. Natalya F. Watson a, 9. Angela Q. Fang a, 10. Hector C. Aguilar a, 11. Matteo Porotto e, 12. Anna N. Honko f, 13. Robert Damoiseaux g, 14. John P. Miller h, 15. Sara E. Woodson b, 16. Steven Chantasirivisal a, 17. Vanessa Fontanes a, 18. Oscar A. Negrete a, 19. Paul Krogstad h, 20. Asim Dasgupta a, 21. Anne Moscona e, 22. Lisa E. Hensley f, 23. Sean P. Whelan d, 24. Kym F. Faull c, 25. Michael R. Holbrook b, 26. Michael E. Jung c, and 27. Benhur Lee a,i,j,3
Author Affiliations
1. aDepartment of Microbiology, Immunology, and Molecular Genetics,
2. cDepartment of Chemistry,
3. gMolecular Shared Screening Resources,
4. hDepartment of Medical and Molecular Pharmacology,
5. iDepartment of Pathology, and
6. jUniversity of California, Los Angeles AIDS Institute, University of California, Los Angeles, CA 90025,
7. bDepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555;
8. dDepartment of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115;
9. fVirology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
10. eWeill Medical College, Cornell University, New York, NY 10021
* ↵2Present address: Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210.
1. Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 29, 2009 (received for review August 24, 2009)
2. ↵1A.N.F., T.Z., and Z.A.-A. contributed equally to this work.
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 the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus?cell but not cell?cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that 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.
* virology
* viral entry
* fusion inhibitor
* small molecule
* lipid membrane
Footnotes
* 3To whom correspondence should be addressed. E-mail: bleebhl@ucla.edu.
* Author contributions: M.C.W., A.N.F., P.K., A.D., A.M., L.E.H., S.P.W., M.R.H., M.E.J., and B.L. designed research; M.C.W., A.N.F., Z.A.-A., A.G., P.W.H., J.L., N.F.W., A.Q.F., H.C.A., M.P., J.P.M., S.E.W., S.C., V.F., K.F.F., and M.R.H. performed research; M.C.W., A.N.F., T.Z., Z.A.-A., J.L., A.N.H., R.D., K.F.F., M.R.H., and M.E.J. contributed new reagents/analytic tools; M.C.W., A.N.F., Z.A.-A., A.G., P.W.H., J.L., N.F.W., A.Q.F., H.C.A., J.P.M., O.A.N., K.F.F., M.R.H., M.E.J., and B.L. analyzed data; and M.C.W., M.R.H., M.E.J., and B.L. wrote the paper.
* The authors declare no conflict of interest.
* This article is a PNAS Direct Submission.
* This article contains supporting information online at www.pnas.org/cgi/content/full/0909587107/DCSupplemental.
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<cite cite="http://www.pnas.org/content/107/7/3157.short?rss=1">A broad-spectrum antiviral targeting entry of enveloped viruses ? PNAS</cite>1. Mike C. Wolf a, 2. Alexander N. Freiberg b,1, 3. Tinghu Zhang c,1, 4. Zeynep Akyol-Ataman a,1, 5. Andrew Grock a, 6. Patrick W. Hong a, 7. Jianrong Li d,2, 8. Natalya F. Watson a, 9. Angela Q. Fang a, 10. Hector C. Aguilar a, 11. Matteo Porotto e, 12. Anna N. Honko f, 13. Robert Damoiseaux g, 14. John P. Miller h, 15. Sara E. Woodson b, 16. Steven Chantasirivisal a, 17. Vanessa Fontanes a, 18. Oscar A. Negrete a, 19. Paul Krogstad h, 20. Asim Dasgupta a, 21. Anne Moscona e, 22. Lisa E. Hensley f, 23. Sean P. Whelan d, 24. Kym F. Faull c, 25. Michael R. Holbrook b, 26. Michael E. Jung c, and 27. Benhur Lee a,i,j,3
Author Affiliations
1. aDepartment of Microbiology, Immunology, and Molecular Genetics,
2. cDepartment of Chemistry,
3. gMolecular Shared Screening Resources,
4. hDepartment of Medical and Molecular Pharmacology,
5. iDepartment of Pathology, and
6. jUniversity of California, Los Angeles AIDS Institute, University of California, Los Angeles, CA 90025,
7. bDepartment of Pathology, University of Texas Medical Branch, Galveston, TX 77555;
8. dDepartment of Microbiology and Molecular Genetics, Harvard Medical School, Boston, MA 02115;
9. fVirology Division, US Army Medical Research Institute of Infectious Diseases, Fort Detrick, MD 21702;
10. eWeill Medical College, Cornell University, New York, NY 10021
* ↵2Present address: Department of Food Science and Technology, The Ohio State University, Columbus, OH 43210.
1. Edited by Peter Palese, Mount Sinai School of Medicine, New York, NY, and approved December 29, 2009 (received for review August 24, 2009)
2. ↵1A.N.F., T.Z., and Z.A.-A. contributed equally to this work.
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 the polar and nonpolar ends of LJ001 in its antiviral activity. LJ001 specifically inhibited virus?cell but not cell?cell fusion, and further studies with lipid biosynthesis inhibitors indicated that LJ001 exploits the therapeutic window that 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.
* virology
* viral entry
* fusion inhibitor
* small molecule
* lipid membrane
Footnotes
* 3To whom correspondence should be addressed. E-mail: bleebhl@ucla.edu.
* Author contributions: M.C.W., A.N.F., P.K., A.D., A.M., L.E.H., S.P.W., M.R.H., M.E.J., and B.L. designed research; M.C.W., A.N.F., Z.A.-A., A.G., P.W.H., J.L., N.F.W., A.Q.F., H.C.A., M.P., J.P.M., S.E.W., S.C., V.F., K.F.F., and M.R.H. performed research; M.C.W., A.N.F., T.Z., Z.A.-A., J.L., A.N.H., R.D., K.F.F., M.R.H., and M.E.J. contributed new reagents/analytic tools; M.C.W., A.N.F., Z.A.-A., A.G., P.W.H., J.L., N.F.W., A.Q.F., H.C.A., J.P.M., O.A.N., K.F.F., M.R.H., M.E.J., and B.L. analyzed data; and M.C.W., M.R.H., M.E.J., and B.L. wrote the paper.
* The authors declare no conflict of interest.
* This article is a PNAS Direct Submission.
* This article contains supporting information online at www.pnas.org/cgi/content/full/0909587107/DCSupplemental.
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