Design of HIV-1 Protease Inhibitors with C3-Substituted Hexahydrocyclopentafuranyl Urethanes as P2-Ligands: Synthesis, Biological Evaluation, and Protein鈥揕igand X-ray Crystal Structure
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- 作者：Arun K. Ghosh ; Bruno D. Chapsal ; Garth L. Parham ; Melinda Steffey ; Johnson Agniswamy ; Yuan-Fang Wang ; Masayuki Amano ; Irene T. Weber ; Hiroaki Mitsuya
- 刊名：Journal of Medicinal Chemistry
- 出版年：2011
- 出版时间：August 25, 2011
- 年：2011
- 卷：54
- 期：16
- 页码：5890-5901
- 全文大小：1038K
- 年卷期：v.54,no.16(August 25, 2011)
- ISSN：1520-4804
文摘
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.