权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

Ess1：一类新型广谱治疗剂的致病真菌靶标

基本信息

批准号：
10324971
负责人：
Stephen Parent
金额：
$ 29.85万
依托单位：
KATHERA BIOSCIENCE INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-17 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10324971
关键词：
Animal Model Animals Antifungal Agents Aspergillus Aspergillus fumigatus Azole resistance Binding Biochemical Biological Sciences Candida Candida albicans Candida auris Cell Survival Cell Wall Cells Cellular Assay Chemicals Chemistry Communicable Diseases Cyclophilins Dependence Development Drug Interactions Drug Targeting Drug resistance Drug toxicity Enzyme Inhibitor Drugs Enzymes Freedom Fungal Drug Resistance Future Genetic Goals Growth Human Human Cell Line Hypersensitivity In Vitro Institutes Intravenous Lead Life Mammalian Cell Membrane Mycoses Oral Orthologous Gene Outcome Pathogenicity Peptidylprolyl Isomerase Pharmaceutical Preparations Phase Program Development Property Research Research Personnel Resistance Resources Series Small Business Innovation Research Grant Specificity Structure Tacrolimus Binding Proteins Testing Therapeutic Agents United States National Institutes of Health Virulence Work analog base chemical genetics clinical Diagnosis clinically relevant combat cytotoxicity drug development druggable target echinocandin resistance effective therapy emerging pathogen improved inhibitor/antagonist lead optimization member multi-drug resistant pathogen mutant novel pathogenic fungus preclinical study programs scaffold screening small molecule small molecule inhibitor symposium synergism

项目摘要

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.

项目总结