title: Design and synthesis of new inhibitors of HIV-1 protease dimerization with conformationally constrained templates.
abstract: To inhibit the HIV-1 protease dimerization necessary to exhibit enzymatic activity, we synthesized and evaluated a new beta-sheet peptide (compound 1), containing 4-(2-aminoethyl)-6-dibenzofuranpropionic acid as a conformationally restricted linker and a non-peptidic beta-strand mimetic, 2-[3-([2-[(9-fluorenylmethoxy)carbonyl]hydrazino]carbonyl)-4-methoxyanilino]-2-oxoacetic acid (Fmoc-Hao-OH, compound 2). Kinetic analysis showed that compound 1 inhibited the dimerization of HIV-1 protease by a dissociative mechanism with a K(id) value of 5.4 microM at 37 degrees C (pH 5.0). However, compound 2 showed a small shift in the slope of the lines in the Zhang-Poorman plot (K(id)=9.1 microM), suggesting that compound 2 inhibits the dimerization of HIV-1 PR not only through a dissociative mechanism but also through an active-site directed mechanism partly. This is the first study of a non-peptidic inhibitor of HIV-1 protease dimerization.
authors.affiliation: Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, 607-8412, Kyoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Song
authors.forename: S
authors.initials: S
authors.lastname: Rajesh
authors.forename: Y
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Y
authors.initials: Y
authors.lastname: Kiso
mesh_terms: D019281:Dimerization; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D016333:HIV Protease / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006834:Hydrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D018716:Molecular Mimicry; D013329:Structure-Activity Relationship
chemical_list: C448400:2-(3-((2-((9-fluorenylmethoxy)carbonyl)hydrazino)carbonyl)-4-methoxyanilino)-2-oxoacetic acid; D017320:HIV Protease Inhibitors; D006834:Hydrazines; D016333:HIV Protease