隐孢子虫特异性 IMP 脱氢酶抑制剂选择性的结构基础。
The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.
机构信息
Departments of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA.
出版信息
J Am Chem Soc. 2010 Feb 3;132(4):1230-1. doi: 10.1021/ja909947a.
Abstract
Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10(3) selectivity for the parasite enzyme over human IMPDH2.
摘要
微小隐孢子虫是一种有潜力的生物战剂，一种重要的艾滋病病原体，也是导致腹泻和营养不良的主要原因。目前尚无疫苗或有效药物来对抗隐孢子虫感染。这种寄生虫依赖肌苷 5'-单磷酸脱氢酶（IMPDH）获取鸟嘌呤核苷酸，而抑制这种酶可以阻止寄生虫的增殖。在这里，我们报告了第一个微小隐孢子虫 IMPDH 的晶体结构。这些结构揭示了抑制剂选择性的结构基础，并提出了进一步优化的策略。利用这些信息，我们已经合成了低纳摩尔的抑制剂，对寄生虫酶相对于人 IMPDH2 具有 10(3)的选择性。
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