Toward the First Nonpeptidic Molecular Tong Inhibitor of Wild-Type and Mutated HIV-1 Protease Dimerization

• Published in: ChemMedChem Vol. 5; no. 11; pp. 1899 - 1906
• Main Authors: Vidu, Anamaria, Dufau, Laure, Bannwarth, Ludovic, Soulier, Jean-Louis, Sicsic, Sames, Piarulli, Umberto, Reboud-Ravaux, Michèle, Ongeri, Sandrine
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 08.11.2010; WILEY‐VCH Verlag
• Subjects: dimerization; HIV Infections - drug therapy; HIV Protease - chemistry; HIV Protease - classification; HIV Protease - genetics; HIV Protease Inhibitors - chemistry; HIV Protease Inhibitors - pharmacology; HIV Protease Inhibitors - therapeutic use; HIV-1; Hydrophobic and Hydrophilic Interactions; inhibitors; Inhibitory Concentration 50; Molecular Mimicry; Mutation - drug effects; Naphthalenes - chemistry; Naphthalenes - pharmacology; Naphthalenes - therapeutic use; peptidomimetics; proteases; Protein Binding - drug effects; Protein Multimerization - drug effects
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201000308

Herein we describe the synthesis and HIV‐1 protease (PR) inhibitory activity of 16 new peptidomimetic molecular tongs with a naphthalene scaffold. Their peptidic character was progressively decreased. Two of these molecules exhibited the best dimerization inhibition activity toward HIV‐1 wild‐type and multimutated ANAM‐11 proteases obtained to date for this class of molecules (∼40 nM for wild‐type PR and 100 nM for ANAM‐11 PR). Although the peptidic character of one molecular tong was completely suppressed, the mechanism of inhibition and inhibitory potency toward both proteases were maintained. Character counts! A set of 16 new peptidomimetic molecular tongs based on a naphthalene scaffold were synthesized and assessed for their inhibitory activity toward HIV‐1 protease. Their peptidic character was progressively decreased, and two compounds exhibited the best dimerization inhibition activity toward HIV‐1 wild‐type and multimutated ANAM‐11 proteases ever observed for this class of molecule.