溶液动力学测量表明，HIV-1蛋白酶对达芦那韦和安普那韦有两个结合位点。
Solution kinetics measurements suggest HIV-1 protease has two binding sites for darunavir and amprenavir.
作者信息
Kovalevsky Andrey Y, Ghosh Arun K, Weber Irene T
机构信息
Departments of Biology and Chemistry, Molecular Basis of Disease Program, Georgia State University, Atlanta, Georgia 30303, USA.
出版信息
J Med Chem. 2008 Oct 23;51(20):6599-603. doi: 10.1021/jm800283k. Epub 2008 Sep 20.
Abstract
Darunavir, a potent antiviral drug, showed an unusual second binding site on the HIV-1 protease dimer surface of the V32I drug resistant mutant and normal binding in the active site cavity. Kinetic analysis for wild type and mutant protease showed mixed-type competitive-uncompetitive inhibition for darunavir and the chemically related amprenavir, while saquinavir showed competitive inhibition. The inhibition model is consistent with the observed second binding site for darunavir and helps to explain its antiviral potency.
摘要
达芦那韦是一种强效抗病毒药物，在V32I耐药突变体的HIV-1蛋白酶二聚体表面显示出一个异常的第二结合位点，并且在活性位点腔中正常结合。对野生型和突变型蛋白酶的动力学分析表明，达芦那韦和化学相关的安普那韦呈现混合型竞争性-非竞争性抑制，而沙奎那韦呈现竞争性抑制。该抑制模型与观察到的达芦那韦的第二结合位点一致，有助于解释其抗病毒效力。
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2
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3
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J Biol Chem. 2007 Sep 28;282(39):28709-28720. doi: 10.1074/jbc.M703938200. Epub 2007 Jul 17.
4
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5
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