DISRUPTION OF EUBACTERIAL 4.5S RNA -P48 COMPLEX

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一类合理设计的小分子抗菌化合物的新靶点。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，并使用分子建模对匹配质量进行评分和排名。得分最低的20000种化合物将在基于邻近闪烁的高通量筛选中进行筛选，以确定它们是否有能力扰乱核糖核酸与蛋白质的相互作用。最具活性的化合物将被选择用于结构-活性研究和第二阶段的进一步合成精化。拟议的商业应用：需要新类别的抗菌化合物来抵消不断发展的抗药性。针对细菌中保守的RNA靶点的新的口服生物利用剂的发现和开发将创造一个重要的市场机会。治疗的目标生物可能包括肺炎球菌、肠球菌和结核病--特别是它们的抗药性菌株。

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.