Giuseppe
Emeritus
Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses (Proc Natl Acad Sci USA, abstract, edited)
[Source: PNAS, <cite cite="http://www.pnas.org/content/107/40/17339.short?rss=1">Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses ? PNAS</cite>. Full text: . Abstract, edited.]
Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses
1. Mireille R. St.Vincent a, 2. Che C. Colpitts b,c, 3. Alexey V. Ustinov d, 4. Muhammad Muqadas a, 5. Michael A. Joyce b,c, 6. Nicola L. Barsby b,c, 7. Raquel F. Epand e, 8. Richard M. Epand e, 9. Stanislav A. Khramyshev d, 10. Olga A. Valueva d, 11. Vladimir A. Korshun d, 12. D. Lorne J. Tyrrell b,c, and 13. Luis M. Schang a,b,c,1
Author Affiliations
1. aDepartment of Biochemistry,
2. bDepartment of Medical Microbiology and Immunology, and
3. cLi Ka Shing Institute of Virology, University of Alberta, Edomonton, AB, Canada T6G 2S2;
4. dThe Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; and
5. eDepartment of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, ON, Canada L8N 3Z5
1. Edited by Leonid Chernomordik, National Institutes of Health, Bethesda, MD, and accepted by the Editorial Board August 18, 2010 (received for review July 12, 2010)
Abstract
Antiviral drugs targeting viral proteins often result in prompt selection for resistance. Moreover, the number of viral targets is limited. Novel antiviral targets are therefore needed. The unique characteristics of fusion between virion envelopes and cell membranes may provide such targets. Like all fusing bilayers, viral envelopes locally adopt hourglass-shaped stalks during the initial stages of fusion, a process that requires local negative membrane curvature. Unlike cellular vesicles, however, viral envelopes do not redistribute lipids between leaflets, can only use the energy released by virion proteins, and fuse to the extracellular leaflets of cell membranes. Enrichment in phospholipids with hydrophilic heads larger than their hydrophobic tails in the convex outer leaflet of vesicles favors positive curvature, therefore increasing the activation energy barrier for fusion. Such phospholipids can increase the activation barrier beyond the energy provided by virion proteins, thereby inhibiting viral fusion. However, phospholipids are not pharmacologically useful. We show here that a family of synthetic rigid amphiphiles of shape similar to such phospholipids, RAFIs (rigid amphipathic fusion inhibitors), inhibit the infectivity of several otherwise unrelated enveloped viruses, including hepatitis C and HSV-1 and -2 (lowest apparent IC50 48 nM), with no cytotoxic or cytostatic effects (selectivity index > 3,000) by inhibiting the increased negative curvature required for the initial stages of fusion.
* lipid bilayer fusion
* DNA virus
* RNA virus
* Sindbis virus
* nucleosides
Footnotes
* 1 To whom correspondence should be addressed. E-mail: luis.schang@ualberta.ca.
* Author contributions: M.R.S., C.C.C., A.V.U., R.F.E., R.M.E., and L.M.S. designed research; M.R.S., C.C.C., A.V.U., M.M., M.A.J., N.L.B., R.F.E., R.M.E., S.A.K., and O.A.V. performed research; V.A.K. and D.L.J.T. contributed new reagents/analytic tools; M.R.S., C.C.C., A.V.U., and L.M.S. analyzed data; and M.R.S., C.C.C., A.V.U., R.F.E., R.M.E., and L.M.S. wrote the paper.
* Conflict of interest statement: M.R.S., A.V.U., and L.M.S. are co-inventors in a series of patent applications describing these discoveries.
* This article is a PNAS Direct Submission. L.C. is a guest editor invited by the Editorial Board.
* See Commentary on page 17069.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1010026107/-/DCSupplemental.
-
------
[Source: PNAS, <cite cite="http://www.pnas.org/content/107/40/17339.short?rss=1">Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses ? PNAS</cite>. Full text: . Abstract, edited.]
Rigid amphipathic fusion inhibitors, small molecule antiviral compounds against enveloped viruses
1. Mireille R. St.Vincent a, 2. Che C. Colpitts b,c, 3. Alexey V. Ustinov d, 4. Muhammad Muqadas a, 5. Michael A. Joyce b,c, 6. Nicola L. Barsby b,c, 7. Raquel F. Epand e, 8. Richard M. Epand e, 9. Stanislav A. Khramyshev d, 10. Olga A. Valueva d, 11. Vladimir A. Korshun d, 12. D. Lorne J. Tyrrell b,c, and 13. Luis M. Schang a,b,c,1
Author Affiliations
1. aDepartment of Biochemistry,
2. bDepartment of Medical Microbiology and Immunology, and
3. cLi Ka Shing Institute of Virology, University of Alberta, Edomonton, AB, Canada T6G 2S2;
4. dThe Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia; and
5. eDepartment of Biochemistry and Biomedical Sciences, McMaster University Health Sciences Centre, Hamilton, ON, Canada L8N 3Z5
1. Edited by Leonid Chernomordik, National Institutes of Health, Bethesda, MD, and accepted by the Editorial Board August 18, 2010 (received for review July 12, 2010)
Abstract
Antiviral drugs targeting viral proteins often result in prompt selection for resistance. Moreover, the number of viral targets is limited. Novel antiviral targets are therefore needed. The unique characteristics of fusion between virion envelopes and cell membranes may provide such targets. Like all fusing bilayers, viral envelopes locally adopt hourglass-shaped stalks during the initial stages of fusion, a process that requires local negative membrane curvature. Unlike cellular vesicles, however, viral envelopes do not redistribute lipids between leaflets, can only use the energy released by virion proteins, and fuse to the extracellular leaflets of cell membranes. Enrichment in phospholipids with hydrophilic heads larger than their hydrophobic tails in the convex outer leaflet of vesicles favors positive curvature, therefore increasing the activation energy barrier for fusion. Such phospholipids can increase the activation barrier beyond the energy provided by virion proteins, thereby inhibiting viral fusion. However, phospholipids are not pharmacologically useful. We show here that a family of synthetic rigid amphiphiles of shape similar to such phospholipids, RAFIs (rigid amphipathic fusion inhibitors), inhibit the infectivity of several otherwise unrelated enveloped viruses, including hepatitis C and HSV-1 and -2 (lowest apparent IC50 48 nM), with no cytotoxic or cytostatic effects (selectivity index > 3,000) by inhibiting the increased negative curvature required for the initial stages of fusion.
* lipid bilayer fusion
* DNA virus
* RNA virus
* Sindbis virus
* nucleosides
Footnotes
* 1 To whom correspondence should be addressed. E-mail: luis.schang@ualberta.ca.
* Author contributions: M.R.S., C.C.C., A.V.U., R.F.E., R.M.E., and L.M.S. designed research; M.R.S., C.C.C., A.V.U., M.M., M.A.J., N.L.B., R.F.E., R.M.E., S.A.K., and O.A.V. performed research; V.A.K. and D.L.J.T. contributed new reagents/analytic tools; M.R.S., C.C.C., A.V.U., and L.M.S. analyzed data; and M.R.S., C.C.C., A.V.U., R.F.E., R.M.E., and L.M.S. wrote the paper.
* Conflict of interest statement: M.R.S., A.V.U., and L.M.S. are co-inventors in a series of patent applications describing these discoveries.
* This article is a PNAS Direct Submission. L.C. is a guest editor invited by the Editorial Board.
* See Commentary on page 17069.
* This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1010026107/-/DCSupplemental.
-
------