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Small molecules that bind the inner core of gp41 and inhibit HIV envelope-mediated fusion.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2006 Sep 19; Vol. 103 (38), pp. 13938-43. Date of Electronic Publication: 2006 Sep 08. - Publication Year :
- 2006
-
Abstract
- HIV-1 enters cells by membrane fusion, mediated by the trimeric viral envelope glycoprotein gp160, which is processed by a single proteolytic cleavage into stably associated gp120 and gp41. The gp120/gp41 trimer can be triggered to undergo an irreversible conformational change. Using a protein-based assay designed to mimic the gp41 conformational change, we screened for small molecules that prevent the formation of postfusion gp41. Several compounds were identified. One set of structurally related molecules inhibited formation of a postfusion-like assembly with an IC50 of approximately 5 microM. The compounds also inhibited envelope-mediated membrane fusion in both cell-cell fusion and viral infectivity assays. Thus, our screen identifies effective fusion inhibitors. Tested against a panel of envelope proteins from primary HIV-1 isolates, the compounds inhibited fusion across a broad range of clades, including both M and T tropic strains. They bind in a highly conserved, hydrophobic pocket on the inner core of the gp41 trimer, a region previously identified as a potential inhibitor site.
- Subjects :
- Amino Acid Sequence
HIV Envelope Protein gp120 chemistry
HIV Envelope Protein gp120 genetics
HIV Envelope Protein gp120 metabolism
HIV Envelope Protein gp41 chemistry
HIV Envelope Protein gp41 genetics
HIV Infections prevention & control
Humans
Models, Molecular
Molecular Structure
Nuclear Magnetic Resonance, Biomolecular
Peptides chemistry
Peptides genetics
Peptides metabolism
Protein Binding
Protein Conformation
Recombinant Fusion Proteins chemistry
Recombinant Fusion Proteins genetics
Recombinant Fusion Proteins metabolism
HIV Envelope Protein gp41 metabolism
HIV-1 metabolism
Membrane Fusion physiology
Virus Internalization
Subjects
Details
- Language :
- English
- ISSN :
- 0027-8424
- Volume :
- 103
- Issue :
- 38
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 16963566
- Full Text :
- https://doi.org/10.1073/pnas.0601036103