TARGETING 4.5S RNA ANTIMICROBIAL DRUG DISCOVERY

针对 4.5S RNA 抗菌药物的发现

• 批准号: 2777500
• 负责人: THOMAS L JAMES
• 金额: $ 10万
• 依托单位: IONIS PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2000-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2777500
• 关键词: antibacterial agents; bacterial RNA; bacterial proteins; combinatorial chemistry; drug discovery /isolation; intermolecular interaction; mathematical model; membrane proteins; protein localization; protein signal sequence; protein structure function; receptor

The conserved eubacterial interaction between 4.5S RNA and protein P48 will be explored as a target for rationally designed small-molecule antimicrobial compounds. The structure of an RNA constituting the P48-binding site in domain IV of 4.5S RNA will be determined using high-resolution NMR spectroscopy. These structures will be used as targets for docking ca. 2X105 compounds from the Available Chemicals Directory and Isis Pharmaceuticals libraries. The compounds will be scored and ranked for quality of fit using molecular modeling. Groups of the lowest scoring 2000 compounds will be screened for their ability to disrupt the RNA-protein interaction in a scintillation proximity-based system. Ten prototype scaffolds will be selected for subsequent synthetic elaboration in Phase II. PROPOSED COMMERCIAL APPLICATION New families of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of a new class of antimicrobial compounds based on a conserved RNA target would generate a significant market opportunity. Therapeutic targets could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.

将探索4.5S RNA与蛋白P48之间保守的真菌性相互作用，作为合理设计小分子抗菌化合物的靶点。构成4.5S RNA结构域IV中p48结合位点的RNA的结构将使用高分辨率核磁共振波谱测定。这些结构将用作对接来自Available Chemicals Directory和Isis Pharmaceuticals文库的约2X105个化合物的靶标。这些化合物将使用分子模型对其匹配质量进行评分和排名。在基于闪烁接近度的系统中，将对得分最低的2000种化合物进行筛选，以确定它们破坏rna -蛋白质相互作用的能力。在第二阶段将选择10个原型支架进行后续的合成加工。建议的商业应用需要新的抗菌化合物家族来抵消正在发展的耐药性。鉴定和开发一类基于保守RNA靶点的新型抗菌化合物将产生重大的市场机会。治疗目标可能包括肺炎球菌、肠球菌和结核病——尤其是它们的耐药菌株。