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

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• 作者：Laure Dufau ; Ana Sofia Marques Ressurrei莽茫o ; Roberto Fanelli ; Nadjib Kihal ; Anamaria Vidu ; Thierry Milcent ; Jean-Louis Soulier ; Jordi Rodrigo ; Audrey Desvergne ; Karine Leblanc ; Guillaume Bernadat ; Benoit Crousse ; Mich猫le Reboud-Ravaux ; Sandrine Ongeri
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：August 9, 2012
• 年：2012
• 卷：55
• 期：15
• 页码：6762-6775
• 全文大小：553K
• 年卷期：v.55,no.15(August 9, 2012)
• ISSN：1520-4804

文摘

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鈥損rotein interactions by reproducing the hydrogen bond pattern found in the antiparallel 尾-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.