Highly Potent HIV-1 Protease Inhibitors with Novel Tricyclic P2 Ligands: Design, Synthesis, and Protein鈥揕igand X-ray Studies
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- 作者：Arun K. Ghosh ; Garth L. Parham ; Cuthbert D. Martyr ; Prasanth R. Nyalapatla ; Heather L. Osswald ; Johnson Agniswamy ; Yuan-Fang Wang ; Masayuki Amano ; Irene T. Weber ; Hiroaki Mitsuya
- 刊名：Journal of Medicinal Chemistry
- 出版年：2013
- 出版时间：September 12, 2013
- 年：2013
- 卷：56
- 期：17
- 页码：6792-6802
- 全文大小：520K
- 年卷期：v.56,no.17(September 12, 2013)
- ISSN：1520-4804
文摘
The design, synthesis, and biological evaluation of a series of HIV-1 protease inhibitors incorporating stereochemically defined fused tricyclic P2 ligands are described. Various substituent effects were investigated to maximize the ligand-binding site interactions in the protease active site. Inhibitors 16a and 16f showed excellent enzyme inhibitory and antiviral activity, although the incorporation of sulfone functionality resulted in a decrease in potency. Both inhibitors 16a and 16f maintained activity against a panel of multidrug resistant HIV-1 variants. A high-resolution X-ray crystal structure of 16a-bound HIV-1 protease revealed important molecular insights into the ligand-binding site interactions, which may account for the inhibitor鈥檚 potent antiviral activity and excellent resistance profiles.