title: Design of potent inhibitors of HIV-1 entry from the gp41 N-peptide region.
abstract: The HIV-1 gp41 envelope glycoprotein promotes fusion of the virus and cell membranes through the formation of a trimer-of-hairpins structure, in which the amino- and carboxyl-terminal regions of the gp41 ectodomain are brought together. Synthetic peptides derived from these two regions (called N and C peptides, respectively) inhibit HIV-1 entry. In contrast to C peptides, which inhibit in the nanomolar range, N peptides are weak inhibitors with IC(50) values in the micromolar range. To test the hypothesis that the weak inhibition of N peptides results from their tendency to aggregate, we have constructed chimeric variants of the N-peptide region of gp41 in which soluble trimeric coiled coils are fused to portions of the gp41 N peptide. These molecules, which present the N peptide in a trimeric coiled-coil conformation, are remarkably more potent inhibitors than the N peptides themselves and likely target the carboxyl-terminal region of the gp41 ectodomain. The best inhibitors described here inhibit HIV-1 entry at nanomolar concentrations.
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Eckert
authors.forename: P S
authors.initials: PS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000821:virology; D002942:Circular Dichroism; D015195:Drug Design; D016368:Frameshift Mutation; D015752:Genes, env; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008156:Luciferases / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry; D014162:Transfection
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides; D011993:Recombinant Fusion Proteins; D008156:Luciferases