Laboratory of Medicinal Chemistry, Faculty of Pharmaceutical Sciences , Kobe Gakuin University , Kobe 650-8586 , Japan.
Department of Medicinal Chemistry , Kyoto Pharmaceutical University , Kyoto 607-8412 , Japan.
J Med Chem. 2018 Jun 28;61(12):5138-5153. doi: 10.1021/acs.jmedchem.7b01709. Epub 2018 Jun 11.
The emergence of drug-resistant HIV from a widespread antiviral chemotherapy targeting HIV protease in the past decades is unavoidable and provides a challenge to develop alternative inhibitors. We synthesized a series of allophenylnorstatine-based peptidomimetics with various P, P, and Ṕ moieties. The derivatives with P tetrahydrofuranylglycine (Thfg) were found to be potent against wild type HIV-1 protease and the virus, leading to a highly potent compound 21f (KNI-1657) against lopinavir/ritonavir- or darunavir-resistant strains. Co-crystal structures of 21f and the wild-type protease revealed numerous key hydrogen bonding interactions with Thfg. These results suggest that the strategy to design allophenylnorstatine-based peptidomimetics combined with Thfg residue would be promising for generating candidates to overcome multidrug resistance.
过去几十年中，广泛使用针对 HIV 蛋白酶的抗病毒化学疗法导致了耐药性 HIV 的出现，这是不可避免的，这对开发替代抑制剂提出了挑战。我们合成了一系列基于别苯基正亮氨酸的具有各种 P、P'和 P"部分的拟肽。具有 P 四氢呋喃基甘氨酸 (Thfg) 的衍生物对野生型 HIV-1 蛋白酶和病毒均具有很强的抑制作用，导致对洛匹那韦/利托那韦或达鲁那韦耐药株具有高度活性的化合物 21f (KNI-1657)。21f 与野生型蛋白酶的共晶结构揭示了与 Thfg 形成的大量关键氢键相互作用。这些结果表明，设计基于别苯基正亮氨酸的拟肽并结合 Thfg 残基的策略对于产生克服多药耐药性的候选药物具有很大的潜力。
