Potent and selective DHFR inhibitors for treating Cryptosporidiosis

描述（由申请人提供）：该STTR申请要求资金支持将特定的生物物理和合成专业知识从康涅狄格大学的安德森和赖特小组转移到Promiliad Biodarma的研究人员，共同努力开发用于治疗隐孢子虫病的一流治疗药物。这种水生原生动物隐孢子虫。代表一种新出现的传染病，并已被列入NIAID的潜在生物防御危害的B级清单。这些努力将集中在二氢叶酸还原酶（DHFR）的抑制剂上，DHFR是一种参与脱氧胸苷单磷酸生产的关键酶，对寄生生物的生存至关重要。虽然抑制这种酶已被证明是对抗疟疾、细菌感染和弓形虫病的成功策略，但用DHFR抑制剂治疗隐孢子虫病还没有成功。由于缺乏任何有效的抗隐孢子虫的药物，因此需要开发这种药物。安德森小组最近解决了来自隐孢子虫的DHFR-TS的晶体结构，并确定了活性位点的几个特征，这些特征可用于设计隐孢子虫DHFR的有效和选择性抑制剂。在与Wright集团和Promiliad Bioreuma的合作中，设计了一系列新型抑制剂，以显示更高水平的效力和选择性。通过这项STTR计划，我们将通过平行合成创建中等规模的新型抑制剂库，筛选这些库中有效和选择性的C。使用体外酶和细胞培养测定法测定人DHFR。我们希望发现几种新的抑制剂，为开发新疗法的II期研究提供基础。

DESCRIPTION (provided by applicant): This STTR application requests funds to support the transfer of specific biophysical and synthetic expertise from the Anderson and Wright Groups at the University of Connecticut to investigators at Promiliad Biopharma in a joint effort to develop best-in-class therapeutic agents for the treatment of cryptosporidiosis. This water-borne protozoan, Cryptosporidium spp. represents an emerging infectious disease and has been placed on NIAID's class B list of potential biodefense hazards. These efforts will focus on inhibitors of dihydrofolate reductase (DHFR), a key enzyme involved in the production of deoxythymidine monophospate and critical for the survival of the parasitic organism. Although inhibition of this enzyme has proven a successful strategy to combat malaria, bacterial infections and toxoplasmosis, there has been no success in treating cryptosporidiosis with DHFR inhibitors. The need for the development of such agents is underscored by the absence of any effective agents against Cryptosporidium. The Anderson group has recently solved the crystal structure of DHFR-TS derived from Cryptosporidium and has identified several features of the active site that can be exploited to design potent and selective inhibitors of Cryptosporidium DHFR. In collaboration with the Wright group and Promiliad Biopharma, a series of novel classes of inhibitors have been designed to display enhanced levels of potency and selectivity. Through this STTR initiative we will create moderately sized libraries of novel inhibitors though parallel synthesis, screen these libraries for potent and selective inhibitors of C. hominis DHFR using in vitro enzyme and cell culture assays. We expect to discover several novel inhibitors that will provide the foundation for Phase II research for the development of new therapeutics.