Ritonavir inhibition of calcium-activated neutral proteases.
Ritonavir inhibition of calcium-activated neutral proteases.
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DOI：
10.1016/s0006-2952(02)00907-3
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发表时间：
2002-04
影响因子：
5.8
通讯作者：
W. Wan;P. DePetrillo
中科院分区：
文献类型：
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作者：
W. Wan;P. DePetrillo
钙蛋白酶是细胞内钙活化的半胱氨酸蛋白酶，介导缺血和创伤后应激后的组织损伤。人类HIV蛋白酶和钙蛋白酶具有相似的二级结构，其中活性位点两侧是疏水区域。目前的研究表明，利托那韦，一种疏水性HIV蛋白酶抑制剂，也能抑制钙蛋白酶活性。在最大活性（2mM钙）的PC12细胞提取物中，利托那韦表现出11±7.0μM的竞争性抑制。纯化酶对m-和μ-calpain均有抑制作用（m-calpain, Ki=9.2±1.2μM; μ-calpain, Ki=5.9±1.4μM）。利托那韦还能原位抑制PC12细胞中钙刺激的钙蛋白酶活性。这些结果表明，利托那韦或该药物类似物应作为细胞保护剂，在通过钙蛋白酶激活介导细胞死亡或损伤的条件下进行研究。
Calpains (EC 3.4.22.17) are intracellular calcium-activated cysteine proteases that mediate tissue injury following post-ischemic and post-traumatic stress. Both human HIV protease and calpains share a similar secondary structure, where the active site is flanked by hydrophobic regions. The present study demonstrates that ritonavir, a hydrophobic HIV protease inhibitor, also inhibits calpain activity. In PC12 cell extracts assayed for calpain at maximal activity (2mM calcium), ritonavir exhibited competitive inhibition with a Kiof 11±7.0μM. Experiments with purified enzymes showed inhibition for both m- and μ-calpain isoforms (m-calpain, Ki=9.2±1.2μM; μ-calpain, Ki=5.9±1.4μM). Ritonavir also inhibited calcium-stimulated calpain activity in PC12 cells in situ. These results suggest that ritonavir or analogues of the drug should be investigated as cytoprotective agents in conditions where cell death or injury is mediated via calpain activation.