title: Selection of gp41-mediated HIV-1 cell entry inhibitors from biased combinatorial libraries of non-natural binding elements.
abstract: The trimeric, alpha-helical coiled-coil core of the HIV-1 gp41 ectodomain is thought to be part of a transient, receptor-triggered intermediate in the refolding of the envelope glycoprotein into a fusion-active conformation. In an effort to discover small organic inhibitors that block gp41 activation, we have generated a biased combinatorial chemical library of non-natural binding elements targeted to the gp41 core. From this library of 61,275 potential ligands, we have identified elements that, when covalently attached to a peptide derived from the gp41 outer-layer alpha-helix, contribute to the formation of a stable complex with the inner core and to inhibition of gp41-mediated cell fusion.
authors.affiliation: Department of Molecular and Cellular Biology, Harvard University, 7 Divinity Ave., Cambridge, Massachusetts 02138, USA.
authors.forename: M
authors.initials: M
authors.lastname: Ferrer
authors.forename: T M
authors.initials: TM
authors.lastname: Kapoor
authors.forename: T
authors.initials: T
authors.lastname: Strassmaier
authors.forename: W
authors.initials: W
authors.lastname: Weissenhorn
authors.forename: J J
authors.initials: JJ
authors.lastname: Skehel
authors.forename: D
authors.initials: D
authors.lastname: Oprian
authors.forename: S L
authors.initials: SL
authors.lastname: Schreiber
authors.forename: D C
authors.initials: DC
authors.lastname: Wiley
authors.forename: S C
authors.initials: SC
authors.lastname: Harrison
mesh_terms: D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002459:Cell Fusion; D002460:Cell Line; D020650:Combinatorial Chemistry Techniques; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008024:Ligands; D008561:Membrane Fusion / Q000187:drug effects*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D019151:Peptide Library; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D008024:Ligands; D010446:Peptide Fragments; D019151:Peptide Library; D011993:Recombinant Fusion Proteins; D000077560:Enfuvirtide