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Nucleocapsid Annealing-Mediated Electrophoresis (NAME) Assay Allows the Rapid Identification of HIV-1 Nucleocapsid Inhibitors
Published on: January 19, 2015
Carbonylhydrazide-based molecular tongs inhibit wild-type and mutated HIV-1 protease dimerization
Laure Dufau1, Ana Sofia Marques Ressurreição, Roberto Fanelli
1UMR-CNRS 8076, Molécules Fluorées et Chimie Médicinale, LabEx LERMIT, Faculté de Pharmacie, Université Paris-Sud 11, 5 rue J. B. Clément, 92296 Châtenay-Malabry Cedex, France.
Abstract:
We have designed and synthesized new molecular tongs based on a rigid naphthalene scaffold and evaluated their antidimer activity on HIV-1 protease (PR). We inserted carbonylhydrazide and oligohydrazide (azatide) fragments into their peptidomimetic arms to reduce hydrophobicity and increase metabolic stability. These fragments are designed to disrupt the protein-protein interactions by reproducing the hydrogen bond pattern found in the antiparallel β-sheet formed between the N- and C-ends of the two monomers in the native PR. Kinetic analyses and fluorescent probe binding studies showed that several molecular tongs can inhibit PR dimerization. The best nonpeptidic molecular tongs to date were obtained with an inhibition constant K(id) of 50 nM for PR and 80 nM for the multimutated protease ANAM-11. The PR inhibition was selective, the aspartic proteases renin and pepsin were not inhibited.
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