title: Non-peptide entry inhibitors of HIV-1 that target the gp41 coiled coil pocket.
abstract: The ectodomain of HIV-1 gp41 mediates the fusion of viral and host cellular membranes. The peptide-based drug Enfuvirtide(1) is precedent that antagonists of this fusion activity may act as anti HIV-agents. Here, NMR screening was used to discover non-peptide leads against this target and resulted in the discovery of a new benzamide 1 series. This series is non-peptide, low molecular weight, and analogs have activity in a cell fusion assay with EC50 values ranging 3-41microM. Structural work on the gp41/benzamide 1 complex was determined by NMR spectroscopy using a designed model peptide system that mimics an open pocket of the fusogenic form of the protein.
authors.affiliation: Pharmaceutical Discovery Division, Abbott Laboratories, 100 Abbott Park Rd., R46Y, AP10, Abbott Park, IL 60064-6098, United States. kent.d.stewart@abbott.com
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Huth
authors.forename: Teresa I
authors.initials: TI
authors.lastname: Ng
authors.forename: Keith
authors.initials: K
authors.lastname: McDaniel
authors.forename: Rebecca Newlin
authors.initials: RN
authors.lastname: Hutchinson
authors.forename: Vincent S
authors.initials: VS
authors.lastname: Stoll
authors.forename: Renaldo R
authors.initials: RR
authors.lastname: Mendoza
authors.forename: Edmund D
authors.initials: ED
authors.lastname: Matayoshi
authors.forename: Robert
authors.initials: R
authors.lastname: Carrick
authors.forename: Hongmei
authors.initials: H
authors.lastname: Mo
authors.forename: Jean
authors.initials: J
authors.lastname: Severin
authors.forename: Karl
authors.initials: K
authors.lastname: Walter
authors.forename: Paul L
authors.initials: PL
authors.lastname: Richardson
authors.forename: Leo W
authors.initials: LW
authors.lastname: Barrett
authors.forename: Robert
authors.initials: R
authors.lastname: Meadows
authors.forename: Steve
authors.initials: S
authors.lastname: Anderson
authors.forename: William
authors.initials: W
authors.lastname: Kohlbrenner
authors.forename: Clarence
authors.initials: C
authors.lastname: Maring
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Kempf
authors.forename: Akhter
authors.initials: A
authors.lastname: Molla
authors.forename: Edward T
authors.initials: ET
authors.lastname: Olejniczak
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001549:Benzamides; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000077560:Enfuvirtide; C037689:benzamide