title: Thyroxine-derivatives of lipopeptides: bifunctional dimerization inhibitors of human immunodeficiency virus-1 protease.
abstract: The structure of new lipopeptides targeting the enzymic dimer interface have been rationally improved resulting in dimerization inhibitors of the human immunodeficiency virus 1 protease (K(id)=5nM for the best inhibitor). The contribution of each amino acid in inhibitory 3-mer lipopeptides was analyzed demonstrating that the C-terminal amino acid residue may preferably be replaced by thyroxine and thyronine. The negative charge of Glu is not essential. Lengthening of the peptidic chain may lead to a decrease of efficiency and a change in the mechanism (competitive inhibition instead of dimerization inhibition). The N-terminal blocking group can be replaced by 2-aminopalmitic acid. The mechanism of inhibition has been ascertained using Zhang's kinetic analysis combined with a physical method based on binding of 1-anilino-8-naphtalene sulfonate to enzyme. By targeting the hydrophobic pocket and the interface antiparallel beta-sheet found relatively free of mutations in contrary to the active site, these efficient dimerization inhibitors may provide a way of overcoming the drug resistances observed with therapeutic antiproteases that bind to the active site.
authors.affiliation: Laboratoire d'Enzymologie Moléculaire et Fonctionnelle, Département de Biologie Cellulaire, Institut Jacques Monod, UMR 7592, CNRS-Universités Paris 6 & 7, 2 Place Jussieu, 75251 Paris Cedex 05, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Dumond
authors.forename: Nicole
authors.initials: N
authors.lastname: Boggetto
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Schramm
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Schramm
authors.forename: Masayuki
authors.initials: M
authors.lastname: Takahashi
authors.forename: Michèle
authors.initials: M
authors.lastname: Reboud-Ravaux
mesh_terms: D000817:Anilino Naphthalenesulfonates / Q000378:metabolism; D019281:Dimerization; D005456:Fluorescent Dyes / Q000378:metabolism; D016333:HIV Protease / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D013974:Thyroxine / Q000737:chemistry
chemical_list: D000817:Anilino Naphthalenesulfonates; D005456:Fluorescent Dyes; D017320:HIV Protease Inhibitors; D010455:Peptides; C027132:1-anilino-8-naphthalenesulfonate; D016333:HIV Protease; D013974:Thyroxine