title: Design, synthesis, and evaluation of conformationally constrained tongs, new inhibitors of HIV-1 protease dimerization.
abstract: The active form of human immunodeficiency virus type 1 protease (HIV-1 PR) is a homodimeric structure in which two subunits are linked through a two-stranded antiparallel beta-sheet consisting of the N- and C-termini of each monomer. To inhibit the dimerization process or disrupt the dimeric interface leading to inactive enzyme, conformationally constrained "molecular tongs" have been designed and synthesized to interfere with one monomer end in a beta-sheet fashion. These molecules are based on two peptidic strands attached to an aromatic scaffold. Inhibitions (submicromolar range) were obtained with molecular tongs containing tripeptidic or tetrapeptidic arms attached to a pyridinediol- or naphthalenediol-based scaffold (Kid = 0.56-4.5 microM at pH 4.7 and 30 degrees C). Kinetic studies are in agreement with an interface inhibition mechanism.
authors: BIOCIS, URA-CNRS 1843, Faculté de Pharmacie, Université de Paris-sud, 5 rue J. B. Clément, F-92296 Châtenay-Malabry Cedex, France.
authors: A
authors: A
authors: Bouras
authors: N
authors: N
authors: Boggetto
authors: Z
authors: Z
authors: Benatalah
authors: E
authors: E
authors: de Rosny
authors: S
authors: S
authors: Sicsic
authors: M
authors: M
authors: Reboud-Ravaux
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry; D019281:Dimerization; D015195:Drug Design; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009281:Naphthalenes; D009842:Oligopeptides; D011725:Pyridines; D016333:HIV Protease