title: Inhibition of HIV type 1 infectivity by constrained alpha-helical peptides: implications for the viral fusion mechanism.
abstract: Linear peptides derived from the membrane proximal region of the gp41 ectodomain are effective inhibitors of HIV type 1 (HIV-1)-mediated fusion events. These inhibitory peptides lack structure in solution, rendering mechanistic interpretation of their activity difficult. Using structurally constrained analogs of these molecules, we demonstrate that the peptides inhibit infectivity by adopting a helical conformation. Moreover, we show that a specific face of the helix must be exposed to block viral infectivity. Recent crystal structures show that the region of gp41 corresponding to the inhibitory peptides is helical and uses the analogous face to pack against a groove formed by an N-terminal coiled-coil trimer. Our results provide a direct link between the inhibition of HIV-1 infectivity by these peptides and the x-ray structures, and suggest that the conformation of gp41 observed by crystallography represents the fusogenic state. Other agents that block HIV-1 infectivity by binding to this groove may hold promise for the treatment of AIDS.
authors.affiliation: Department of Bioorganic Chemistry, Genentech, Inc., 460 Point San Bruno Boulevard, South San Francisco, CA 94080, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Judice
authors.forename: J Y
authors.initials: JY
authors.lastname: Tom
authors.forename: W
authors.initials: W
authors.lastname: Huang
authors.forename: T
authors.initials: T
authors.lastname: Wrin
authors.forename: J
authors.initials: J
authors.lastname: Vennari
authors.forename: C J
authors.initials: CJ
authors.lastname: Petropoulos
authors.forename: R S
authors.initials: RS
authors.lastname: McDowell
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002942:Circular Dichroism; D018360:Crystallography, X-Ray; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity*; D006801:Humans; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000821:virology; D008561:Membrane Fusion / Q000187:drug effects / Q000502:physiology; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship; D014774:Virulence / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments