A Redesigning Existing Drugs against Indispensable Targets (ReEDIT) platform technology for discovery of novel drugs to treat fungal infections

项目摘要 全世界都需要改善对危及生命的全身性真菌感染的治疗。 目前的治疗方法受到批准药物数量少、毒性、药物间相互作用等因素的限制。 相互作用、给药方式以及日益严重的耐药性问题和新出现的 病原体治疗也因缺乏快速的临床诊断而受到影响，导致依赖性 广谱抗真菌药物此外，现有的抗真菌药物类靶向膜 和细胞壁完整性，并且需要开发具有新作用模式的药物。基本 基因是有吸引力的抗真菌药物靶点，因为它们是真菌病原体生长所必需的 和生存C.白色念珠菌是人类主要的真菌病原体， 病原真菌中的工具。我们建议“重新设计现有药物， Inhibitors Targets”（ReEDIT）策略，重点关注C.白色念珠菌， 具有保守的人类直系同源物，其具有已知的化学易处理抑制剂（CTI）， 批准的药物或处于临床或临床前开发中。ReEDIT是一种综合方法 使用抗真菌生长敏感性、生物化学、结构、生物信息学和化学信息学 数据，以及分子建模研究，以优先考虑潜在的真菌目标。具体目标 第一阶段的建议是（1）确定致病真菌中编码 可药物化的目标和（2）推进至少一个基本目标和药物系列进入铅 优化.结果将推进一个或少数重要的真菌靶标， 候选药物纳入先导药物优化和临床前研究计划（II期）。的 长期目标是将新型必需真菌蛋白的抑制剂开发成新的类别 广谱抗真菌药物的研究据我们所知，这是第一次系统地研究 评估一套全面的保守的重要真菌基因和同源抑制剂 用于抗真菌药物的研发

Project Summary There is a worldwide 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 with new modes of action. Essential genes are attractive antifungal drug targets because they are required for fungal pathogen growth and survival. C. albicans is the major human fungal pathogen and has the most robust genetic tools among the pathogenic fungi. We propose a “Redesigning Existing Drugs against Indispensable Targets” (ReEDIT) strategy that focuses on essential genes in C. albicans that have conserved human orthologs with known Chemically Tractable Inhibitors (CTIs) that are approved drugs or are in clinical or preclinical development. ReEDIT is an integrative approach using antifungal growth susceptibility, biochemical, structural, bioinformatic, and cheminformatic data, as well as molecular modeling studies to prioritize potential fungal targets. The specific aims of this Phase I proposal are to (1) identify essential genes in pathogenic fungi that encode druggable targets and (2) advance at least one essential target and drug series into lead optimization. The outcome will advance one or a small number of essential fungal targets and drug candidate(s) into a program for lead optimization and pre-clinical studies (Phase II). The long-term objectives are to develop inhibitors of novel essential fungal proteins into new classes of broad-spectrum antifungal drugs. To our knowledge, this is the first study to systematically assess a comprehensive set of conserved essential fungal genes and cognate inhibitors to be advanced for antifungal drug development.