COPPER INHIBITS THE PROTEASE FROM HUMAN IMMUNODEFICIENCY VIRUS-1 BY BOTH CYSTEINE-DEPENDENT AND CYSTEINE-INDEPENDENT MECHANISMS
COPPER INHIBITS THE PROTEASE FROM HUMAN IMMUNODEFICIENCY VIRUS-1 BY BOTH CYSTEINE-DEPENDENT AND CYSTEINE-INDEPENDENT MECHANISMS
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DOI：
10.1073/pnas.88.13.5552
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发表时间：
1991-07-01
影响因子：
11.1
通讯作者：
LEVINE, RL
中科院分区：
文献类型：
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作者：
KARLSTROM, AR;LEVINE, RL
人类免疫缺陷病毒的蛋白酶是病毒复制所必需的，因此该酶是抗病毒作用的有吸引力的靶标。我们已经发现，病毒蛋白酶被大约化学计量浓度的铜或汞离子抑制。由Cu 2+灭活是迅速的，并没有逆转随后暴露于EDTA或二硫苏糖醇。Cu 2+的直接抑制需要蛋白酶中存在半胱氨酸残基。因此，缺乏半胱氨酸残基的合成蛋白酶不受铜暴露的抑制。然而，添加二硫苏糖醇作为外源性硫醇使得甚至合成的蛋白酶容易被铜灭活。野生型或合成蛋白酶的失活都不需要氧气。这些结果为新型蛋白酶抑制剂的设计提供了基础。
The protease of the human immunodeficiency virus is essential for replication of the virus, and the enzyme is therefore an attractive target for antiviral action. We have found that the viral protease is inhibited by approximately stoichiometric concentrations of copper or mercury ions. Inactivation by Cu2+ was rapid and not reversed by subsequent exposure to EDTA or dithiothreitol. Direct inhibition by Cu2+ required the presence of cysteine residue(s) in the protease. Thus, a synthetic protease lacking cysteine residues was not inhibited by exposure to copper. However, addition of dithiothreitol as an exogenous thiol rendered even the synthetic protease susceptible to inactivation by copper. Oxygen was not required for inactivation of either the wild-type or the synthetic protease. These results provide the basis for the design of novel types of protease inhibitors.