DISRUPTION OF EUBACTERIAL 4.5S RNA -P48 COMPLEX

真细菌 4.5S RNA -P48 复合物的破坏

• 批准号: 6015182
• 负责人: RICHARD H GRIFFEY
• 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: 1999-09-15 至 2000-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6015182
• 关键词: RNA; antibiotics; chemical models; combinatorial chemistry; drug design /synthesis /production; drug screening /evaluation; intermolecular interaction; nucleic acid structure; protein binding; protein signal sequence; protein structure; receptor

The eubacterial signal recognition particle, comprised of a 4.5S RNA and protein P48, will be explored as a new class of target for rationally designed small-molecule antimicrobial compounds. Compounds from the Available Chemicals Directory and Isis Pharmaceuticals libraries will be docked against the RNA structures, and scored and ranked for quality of fit using molecular modeling. The lowest scoring 20000 compounds will be screened for their ability to disrupt the RNA-protein interaction in a scintillation proximity-based high through-put screen. The most active compounds will be selected for structure-activity studies and further synthetic elaboration in Phase II. PROPOSED COMMERCIAL APPLICATIONS: New classes of antimicrobial compounds are needed to offset developing drug resistance. Identification and development of new orally bioavailable agents against a conserved RNA target in bacteria would generate a significatmarket opportunity. Therapeutic target organisms could include pneumococci, enterococci, and tuberculosis - especially their drug-resistant strains.

由4.5S RNA和蛋白质P48组成的真细菌信号识别颗粒将被探索为合理设计的小分子抗微生物化合物的一类新靶标。来自可用化学品目录和Isis制药库的化合物将与RNA结构对接，并使用分子建模对拟合质量进行评分和排名。最低得分的20000种化合物将在基于闪烁邻近度的高通量筛选中筛选其破坏RNA-蛋白质相互作用的能力。将选择活性最高的化合物进行结构-活性研究，并在第II阶段进一步合成。拟议的商业应用：需要新类别的抗菌化合物来抵消正在形成的耐药性。针对细菌中保守的RNA靶点的新的口服生物可利用剂的鉴定和开发将产生重大的市场机会。治疗靶生物可能包括肺炎球菌、肠球菌和结核病--特别是它们的耐药菌株。