Structure-Based Approach to the Development of Potent and Selective Inhibitors of Dihydrofolate Reductase from Cryptosporidium
Structure-Based Approach to the Development of Potent and Selective Inhibitors of Dihydrofolate Reductase from Cryptosporidium
复制标题
DOI：
10.1021/jm8009124
复制
发表时间：
2008-11-13
影响因子：
7.3
通讯作者：
Anderson, Amy C.
中科院分区：
文献类型：
--
作者：
Bolstad, David B.;Bolstad, Erin S. D.;Anderson, Amy C.
隐孢子虫病是一种新出现的传染病，可能会危及所有免疫功能低下的个体的生命，并导致免疫功能正常的个体出现长达两周的胃肠道不适。可有效治疗这种疾病的疗法很少。我们一直在探索二氢叶酸还原酶（DHFR）作为隐孢子虫的潜在靶点。根据人型线虫 DHFR 酶的结构，我们开发了一种新型支架，从而发现了该酶的强效 (38 nM) 抑制剂。最近，我们已将这些抑制剂推进到下一开发阶段。使用原生动物和人类酶的结构。我们开发了针对致病酶具有纳摩尔效力 (1.1 nM) 的抑制剂，并且对人类酶具有高水平（1273 倍）选择性。
Cryptosporidiosis is an emerging infectious disease that can be life-threatening in ail immune-compromised individual and causes gastrointestinal distress lasting up to 2 weeks in an immune-competent individual. There are few therapeutics available for effectively treating this disease. We have been exploring dihydrofolate reductase (DHFR) as a potential target in Cryptosporidium. On the basis of the structure of the DHFR enzyme from C. hominis, we have developed a novel scaffold that led to the discovery of potent (38 nM) and efficient inhibitors of this enzyme. Recently, we have advanced these inhibitors to the next stage of development. Using the Structures of both the protozoal and human enzymes. we have developed inhibitors with nanomolar potency (1.1 nM) against the pathogenic enzyme and high levels (1273-fold) of selectivity over the human enzyme.