Structure-based design of novel HIV-1 protease inhibitors to combat drug resistance

被引:115
作者
Ghosh, Arun K. [1 ]
Sridhar, Perali Ramu
Leshchenko, Sofiya
Hussain, Azhar K.
Li, Jianfeng
Kovalevsky, Andrey Yu.
Walters, D. Eric
Wedekind, Joseph E.
Grum-Tokars, Valerie
Das, Debananda
Koh, Yasuhiro
Maeda, Kenji
Gatanaga, Hiroyuki
Weber, Irene T.
Mitsuya, Hiroaki
机构
[1] Purdue Univ, Dept Chem, W Lafayette, IN 47907 USA
[2] Purdue Univ, Dept Med Chem, W Lafayette, IN 47907 USA
[3] Georgia State Univ, Dept Biol Mol Basis Dis, Atlanta, GA 30303 USA
[4] Rosalind Franklin Univ Med & Sci, Dept Biochem & Mol Biol, Abbott Pk, IL 60064 USA
[5] Kumamoto Univ, Sch Med, Dept Hematol, Kumamoto 8608556, Japan
[6] Kumamoto Univ, Sch Med, Dept Infect Dis, Kumamoto 8608556, Japan
[7] NCI, Expt Retrovirol Sect, HIV & AIDS Malignancy Branch, Bethesda, MD 20892 USA
关键词
D O I
10.1021/jm060561m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Structure-based design and synthesis of novel HIV protease inhibitors are described. The inhibitors are designed specifically to interact with the backbone of HIV protease active site to combat drug resistance. Inhibitor 3 has exhibited exceedingly potent enzyme inhibitory and antiviral potency. Furthermore, this inhibitor maintains impressive potency against a wide spectrum of HIV including a variety of multi-PI-resistant clinical strains. The inhibitors incorporated a stereochemically defined 5-hexahydrocyclopenta[b]furanyl urethane as the P2-ligand into the (R)-(hydroxyethylamino) sulfonamide isostere. Optically active (3aS,5R,6aR)-5-hydroxy-hexahydrocyclopenta[b] furan was prepared by an enzymatic asymmetrization of meso-diacetate with acetyl cholinesterase, radical cyclization, and Lewis acid-catalyzed anomeric reduction as the key steps. A protein-ligand X-ray crystal structure of inhibitor 3-bound HIV-1 protease (1.35 angstrom resolution) revealed extensive interactions in the HIV protease active site including strong hydrogen bonding interactions with the backbone. This design strategy may lead to novel inhibitors that can combat drug resistance.
引用
收藏
页码:5252 / 5261
页数:10
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