Carbonylhydrazide-Based Molecular Tongs Inhibit Wild-Type and Mutated HIV-1 Protease Dimerization

Laure Dufau , Ana Sofia Marques Ressurreicao , Roberto Fanelli , Nadjib Kihal , Anamaria Vidu , Thierry Milcent , Jean-Louis Soulier , Jordi Rodrigo , Audrey Desyergne , Karine Leblanc , Guillaume Bernadat , Benoit Crousse , Michele Reboud-Ravaux (1) , Sandrine Ongeri

1 VCII - Vieillissement Cellulaire Intégré et Inflammation

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 beta-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.

Domaines: Biologie cellulaire

Laure Dufau, Ana Sofia Marques Ressurreicao, Roberto Fanelli, Nadjib Kihal, Anamaria Vidu, et al.. Carbonylhydrazide-Based Molecular Tongs Inhibit Wild-Type and Mutated HIV-1 Protease Dimerization. Journal of Medicinal Chemistry, 2012, 55 (15), pp.6762-6775. ⟨10.1021/jm300181j⟩. ⟨hal-01544073⟩