Crystallographic study of multi-drug resistant HIV-1 protease lopinavir complex: Mechanism of drug recognition and resistance

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• 作者：Zhigang Liu ; Ravikiran S. Yedidi ; Yong Wang ; Tamaria G. Dewdney ; Samuel J. Reiter ; Joseph S. Brunzelle ; Iulia A. Kovari ; Ladislau C. Kovari
• 关键词：MDR ; multi-drug resistance ; HAART ; highly active anti-retroviral therapy ; LPV ; lopinavir ; IC50 ; half maximal inhibitory concentration ; RMSD ; root mean square deviation
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2013
• 出版时间：26 July, 2013
• 年：2013
• 卷：437
• 期：2
• 页码：199-204
• 全文大小：1419 K

文摘

Lopinavir (LPV) is a second generation HIV-1 protease inhibitor. Drug resistance has rapidly emerged against LPV since its US FDA approval on September 15, 2000. Mutations at residues 32I, L33F, 46I, 47A, I54V, V82A, I84V, and L90M render the protease drug resistant against LPV. We report the crystal structure of a clinical isolate multi-drug resistant (MDR) 769 HIV-1 protease (resistant mutations at residues 10, 36, 46, 54, 62, 63, 71, 82, 84, and 90) complexed with LPV and the in vitro enzymatic IC₅₀ of LPV against MDR 769. The structural and functional studies demonstrate significant drug resistance of MDR 769 against LPV, arising from reduced interactions between LPV and the protease target.