Target-based antifungal drug discovery

基于靶点的抗真菌药物发现

• 批准号: 6700777
• 负责人: JOHN D. TRAWICK
• 金额: $ 23.54万
• 依托单位: ELITRA PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-15 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6700777
• 关键词: Candida albicans; antifungal agents; candidiasis; chemical registry /resource; drug discovery /isolation; drug receptors; drug screening /evaluation; expression cloning; fungal genetics; gene expression; genetic library; genetic screening

DESCRIPTION (provided by applicant): The incidence of serious fungal infections has increased markedly in the last two decades and effective treatment options are increasingly compromised by the emergence of drug-resistant strains. The goal of the proposed work is to develop novel antifungal drugs that are safer and more effective than those currently available. The work will focus primarily on the dimorphic yeast, C. albicans, which is by far the leading cause of both life-threatening systemic fungal infections and more commonly occurring topical infections. A distinguishing feature of the drug-discovery strategy the applicants are pursuing is that it is based on target discovery, target prioritization and screening, all conducted with the pathogen itself, rather than with a surrogate model system. This strategy has been enabled by gene-identification and screen-configuration technologies developed at Elitra Pharmaceuticals, including important technologies developed under Phase I funding for this program. Under Phase I, an expression vector system was constructed that will allow screening for dominant-negative phenotypes. No such tools existed previously for C. albicans. Screens for dominant-negatives will identify new drug targets in C. albicans and help annotate essential physiological pathways in this important fungal pathogen. Critical functional features of the expression vector system have already been validated, a C. albicans complementary deoxyribonucleic acid (cDNA) library has been constructed in the vector, and pilot screening for dominant-negatives is in progress. Under Phase II funding, the investigators propose to implement the screen more broadly, characterize and prioritize the targets that are identified and conduct screening for drug leads. The dominant-negative phenotypes of the newly identified targets will be used to develop primary or secondary cell-based assays to screen chemical libraries for potential antifungal drugs and to facilitate the characterization of hits identified through other screening strategies. The proposed Phase II work will complement and enhance the value of internally funded target-identification and screening efforts at Elitra and will help promote the discovery of badly needed therapeutic agents in a medical area that generally receives insufficient attention from the pharmaceutical industry.

描述（由申请人提供）：过去二十年中，严重真菌感染的发病率显着增加，有效的治疗方案因耐药菌株的出现而日益受到影响。 拟议工作的目标是开发比现有药物更安全、更有效的新型抗真菌药物。 这项工作将主要集中在二态性酵母菌白色念珠菌上，它是迄今为止威胁生命的全身真菌感染和更常见的局部感染的主要原因。 申请人所追求的药物发现策略的一个显着特征是，它基于靶点发现、靶点优先排序和筛选，所有这些都是针对病原体本身而不是替代模型系统进行的。 该战略是通过 Elitra Pharmaceuticals 开发的基因识别和屏幕配置技术实现的，其中包括在该项目第一阶段资助下开发的重要技术。 在第一阶段，构建了一个表达载体系统，可以筛选显性失活表型。 以前不存在针对白色念珠菌的此类工具。 显性失活筛选将识别白色念珠菌中的新药物靶点，并帮助注释这种重要真菌病原体的基本生理途径。 表达载体系统的关键功能特征已经得到验证，白色念珠菌互补脱氧核糖核酸（cDNA）文库已在载体中构建，显性失活的初步筛选正在进行中。 在第二阶段的资助下，研究人员建议更广泛地实施筛选，对已确定的目标进行表征和优先排序，并对先导药物进行筛选。 新确定的靶标的显性失活表型将用于开发初级或次级细胞测定法，以筛选化学库中潜在的抗真菌药物，并促进通过其他筛选策略确定的命中的表征。拟议的第二阶段工作将补充和增强 Elitra 内部资助的靶标识别和筛选工作的价值，并将有助于促进在制药行业普遍关注不足的医疗领域发现急需的治疗药物。