title: Structure-based design of substituted biphenyl ethylene ethers as ligands binding in the hydrophobic pocket of gp41 and blocking the helical bundle formation.
abstract: A series of substituted biphenyl ethylene ether compounds has been designed to target the gp41N-trimer in order to inhibit formation of the six-helical bundle that represents the end state of gp41-mediated viral fusion. A size exclusion HPLC based helical bundle formation (HBF) assay was developed to evaluate in vitro inhibitory affinity of the inhibitors. The most potent compound 1 had an IC(50) of 31microM. The binding of compound 1 to the proposed hydrophobic pocket of gp41 was further validated by site-directed peptide mutagenesis experiments.
authors.affiliation: Locus Pharmaceuticals, Inc., Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA. bliu@locuspharma.com
authors.forename: Bin
authors.initials: B
authors.lastname: Liu
authors.forename: Rhoda W
authors.initials: RW
authors.lastname: Joseph
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Dorsey
authors.forename: Robert A
authors.initials: RA
authors.lastname: Schiksnis
authors.forename: Katrina
authors.initials: K
authors.lastname: Northrop
authors.forename: Marina
authors.initials: M
authors.lastname: Bukhtiyarova
authors.forename: Eric B
authors.initials: EB
authors.lastname: Springman
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D004987:Ethers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015700:HIV Envelope Protein gp41 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013777:Tetrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D004987:Ethers; D015700:HIV Envelope Protein gp41; D008024:Ligands; D009281:Naphthalenes; D013777:Tetrazoles