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

项目摘要 全世界都需要改进系统性、危及生命的真菌感染的治疗。 目前的治疗受到少数批准的药物、毒性、药物-药物的限制 相互作用、给药模式、日益严重的耐药性问题和新出现的问题 病原体。治疗也缺乏快速的临床诊断，导致依赖。 广谱抗真菌药物。此外，现有的抗真菌药物类别以膜为靶标 和细胞壁的完整性，需要开发具有新作用模式的药物。基本要素 基因是吸引人的抗真菌药物靶点，因为它们是真菌病原体生长所必需的 和生存。白色念珠菌是人类主要的真菌病原体，具有最健壮的基因 病原真菌之间的工具。我们建议对现有药物进行重新设计，以对抗 关注白色念珠菌基本基因的“不可或缺的靶点”(重新编辑)策略 用已知的化学上易处理的抑制剂(CTI)保存了人类同源物 已批准的药物或正在进行临床或临床前开发。重新编辑是一种综合的方法 使用抗真菌生长敏感性、生化、结构、生物信息学和化学信息学 数据，以及分子建模研究，以确定潜在的真菌目标的优先顺序。具体目标 这一阶段第一阶段的建议是：(1)确定病原真菌中编码 可药物靶点和(2)将至少一个基本靶点和药物系列推进到铅 优化。结果将推进一个或少数重要的真菌靶标和 候选药物(S)进入先导优化和临床前研究计划(第二阶段)。这个 长期目标是将新的基本真菌蛋白的抑制剂开发成新的类别 广谱抗真菌药物。据我们所知，这是第一次系统地研究 评估一组保守的基本真菌基因和同源抑制剂 在抗真菌药物开发方面处于领先地位。

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.