C3-取代的六氢环戊呋喃基尿嘧啶类作为 P2-配体的 HIV-1 蛋白酶抑制剂的设计：合成、生物评价及蛋白-配体 X 射线晶体结构。
Design of HIV-1 protease inhibitors with C3-substituted hexahydrocyclopentafuranyl urethanes as P2-ligands: synthesis, biological evaluation, and protein-ligand X-ray crystal structure.
机构信息
Department of Chemistry, Purdue University, West Lafayette, Indiana 47907, USA.
出版信息
J Med Chem. 2011 Aug 25;54(16):5890-901. doi: 10.1021/jm200649p. Epub 2011 Jul 29.
Abstract
We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26 containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26 exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions.
摘要
我们报告了一种新型 HIV-1 蛋白酶抑制剂的设计、合成、生物评价以及 X 射线晶体结构。各种 C3-功能化的环戊烷四氢呋喃（Cp-THF）被设计用来与 HIV-1 蛋白酶的瓣状 Gly48 羰基或酰胺 NH 相互作用。我们研究了这些功能化配体与羟乙基磺酰胺等排体结合的潜力。含有 Cp-THF 核上 3-(R)-羟基的抑制剂 26 显示出最强的酶抑制和抗病毒活性。我们的研究表明，3-(R)-构型比相应的 3-(S)-衍生物更具优势。抑制剂 26 对多种耐药性 HIV-1 变体表现出很强的活性。26 结合的 HIV-1 蛋白酶的高分辨率 X 射线结构揭示了配体结合位点相互作用的重要分子见解。
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