title: Inhibiting HIV-1 entry: discovery of D-peptide inhibitors that target the gp41 coiled-coil pocket.
abstract: The HIV-1 gp41 protein promotes viral entry by mediating the fusion of viral and cellular membranes. A prominent pocket on the surface of a central trimeric coiled coil within gp41 was previously identified as a potential target for drugs that inhibit HIV-1 entry. We designed a peptide, IQN17, which properly presents this pocket. Utilizing IQN17 and mirror-image phage display, we identified cyclic, D-peptide inhibitors of HIV-1 infection that share a sequence motif. A 1.5 A cocrystal structure of IQN17 in complex with a D-peptide, and NMR studies, show that conserved residues of these inhibitors make intimate contact with the gp41 pocket. Our studies validate the pocket per se as a target for drug development. IQN17 and these D-peptide inhibitors are likely to be useful for development and identification of a new class of orally bioavailable anti-HIV drugs.
authors.affiliation: Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, Cambridge 02142, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Eckert
authors.forename: V N
authors.initials: VN
authors.lastname: Malashkevich
authors.forename: L H
authors.initials: LH
authors.lastname: Hong
authors.forename: P A
authors.initials: PA
authors.lastname: Carr
authors.forename: P S
authors.initials: PS
authors.lastname: Kim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D003461:Crystallography; D015700:HIV Envelope Protein gp41 / Q000737:chemistry*; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D015497:HIV-1 / Q000737:chemistry*; D017912:Inovirus; D009682:Magnetic Resonance Spectroscopy; D008561:Membrane Fusion / Q000187:drug effects; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010455:Peptides