Bannwarth Ludovic, Kessler Albane, Pèthe Stéphanie, Collinet Bruno, Merabet Naïma, Boggetto Nicole, Sicsic Sames, Reboud-Ravaux Michèle, Ongeri Sandrine
Université de Paris-Sud XI, IFR 141, Biocis, UMR-CNRS 8076, Faculté de Pharmacie, 5 Rue J. B. Clément, F-92296 Châtenay-Malabry Cedex, France.
J Med Chem. 2006 Jul 27;49(15):4657-64. doi: 10.1021/jm060576k.
We have designed, synthesized, and evaluated the inhibitory activity and metabolic stability of new peptidomimetic molecular tongs based on a naphthalene scaffold for inhibiting HIV-1 protease dimerization. Peptidomimetic motifs were inserted into one peptidic strand to make it resistant to proteolysis. The peptidic character of the molecular tongs can be decreased without changing the way they inhibit dimerization. Mutated HIV-1 proteases are also vulnerable to dimerization inhibitors, and the multimutated protease ANAM-11 is twice as sensitive to the inhibitor compared to wild-type protease. Thus, the metabolic stability of antidimeric molecular tongs can be increased without compromising their ability to inhibit wild-type and mutated HIV-1 proteases in vitro.
我们设计、合成并评估了基于萘支架的新型拟肽分子钳的抑制活性和代谢稳定性，以抑制HIV-1蛋白酶二聚化。将拟肽基序插入一条肽链中，使其具有抗蛋白水解能力。在不改变分子钳抑制二聚化方式的情况下，可以降低其肽性。突变的HIV-1蛋白酶也易受二聚化抑制剂的影响，与野生型蛋白酶相比，多突变蛋白酶ANAM-11对该抑制剂的敏感性是其两倍。因此，可以提高抗二聚体分子钳的代谢稳定性，同时不影响其在体外抑制野生型和突变型HIV-1蛋白酶的能力。
