Ess1: A pathogenic fungal target for a novel class of broad-spectrum therapeutic agents

项目摘要 全世界都需要改善对全身性、危及生命的真菌感染的治疗。 感染.目前的治疗方法受到批准的药物数量少、毒性、药物- 药物相互作用、给药方式和日益严重的耐药性问题， 新兴病原体治疗还缺乏快速的临床诊断，导致 对广谱抗真菌药物的依赖。此外，现有的抗真菌药物类别 靶向膜和细胞壁完整性，并且需要开发针对靶点的药物 with new新models模式of action行动.现有的证据表明，E101可能是这样一个目标。101是 一种在真菌病原体（包括念珠菌）中高度保守的必需脯氨酰异构酶 白色念珠菌和烟曲霉，其作用机制是互补的，因为它 与现有抗真菌药物的靶点不重叠。几个小分子“命中”， 已经鉴定了与EST 1突变细胞的化学-遗传相互作用， 结构与其人类直系同源物（Pin 1）的差异足以表明 选择性β 1抑制剂是可行的。第一阶段建议的具体目标是：（1） 验证作为药物靶点的抑制剂1，以及（2）鉴定化学上 “命中领先”药物开发项目的可行性该方法将使用生物化学和 全细胞试验，以测试针对P171和Pin 1酶、真菌病原体的抑制剂，以及 哺乳动物细胞，并开发一个强大的探索性化学计划，以实现这些 目标。这些结果将推动该计划进入到命中到铅，铅优化和临床前 研究（II期）。长期目标是将BMP 1抑制剂开发成一类新的药物， 广谱抗真菌药物

Project Summary There is a world-wide need for improved treatment of systemic, life-threatening fungal infections. Current therapies are limited by the small number of approved drugs, toxicities, drug- drug interactions, mode of administration, and growing problems of drug resistance and emerging pathogens. Treatment also suffers from a lack of rapid clinical diagnoses, leading to dependence on broad-spectrum antifungal drugs. Moreover, existing antifungal drug classes target membrane and cell wall integrity, and there is a need to develop drugs against targets with new modes of action. Available evidence suggest Ess1 might be one such target. Ess1 is an essential prolyl isomerase that is highly conserved in fungal pathogens, including Candida albicans and Aspergillus fumigatus, and its mechanism-of-action is complementary in that it does not overlap with targets of existing antifungals. Several small molecule "hits" that show chemical-genetic interactions with Ess1 mutant cells have been identified, and fungal Ess1 structure differs sufficiently from its human ortholog (Pin1) to suggest that development of selective Ess1 inhibitors is feasible. The specific aims of this Phase I proposal are to (1) validate Ess1 as a druggable target and (2) identify inhibitor scaffolds that are chemically tractable for a "hit to lead" drug development program. The approach will use biochemical and whole-cell assays to test inhibitors against Ess1 and Pin1 enzymes, fungal pathogens, and mammalian cells, and to develop a robust exploratory chemistry program to accomplish these aims. The outcomes will advance this program into hit-to-lead, lead optimization and pre-clinical studies (Phase II). The long-term objective is to develop Ess1 inhibitors into a new class of broad-spectrum antifungal drugs.