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

项目摘要 全世界都需要改进对系统性、危及生命的真菌的治疗。 感染。目前的治疗方法受到批准的药物数量较少、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 新出现的病原体。治疗也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 靶膜和细胞壁的完整性，有必要开发针对靶点的药物 有了新的行动模式。现有证据表明，Ess1可能是这样的目标之一。Ess1是 一种必需的脯氨酰异构酶，在包括念珠菌在内的真菌病原体中高度保守 白念珠菌和烟曲霉，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“击中”了那个节目 已经确定了与Ess1突变细胞的化学-遗传相互作用，真菌Ess1 其结构与其人类同源基因(Pin1)有很大的不同，表明 选择性Ess1抑制剂是可行的。这项第一阶段提案的具体目标是：(1) 确认Ess1为可用药目标，以及(2)确定化学上具有 对于一个“由打到领导”的药物开发计划来说，这是一个容易处理的问题。该方法将使用生化和 全细胞试验以测试抑制Ess1和Pin1酶、真菌病原体和 哺乳动物细胞，并开发一个强大的探索性化学计划来完成这些 目标。结果将推动该计划进入点击到领先、领先优化和临床前阶段 研究(第二阶段)。长期目标是将Ess1抑制剂开发成一种新的 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.