TARGETING 4.5S RNA ANTIMICROBIAL DRUG DISCOVERY

4.5S RNA与P48蛋白之间保守的优菌相互作用将成为合理设计小分子抗菌化合物的靶点。组成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光谱来确定。这些结构将被用作从现有的化学品目录和ISIS制药图书馆中对接大约2X105种化合物的目标。这些化合物将使用分子建模进行评分和匹配质量排名。得分最低的2000种化合物的分组将被筛选，以确定它们在基于邻近闪烁的系统中扰乱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精加工。拟议的商业应用需要新的抗菌化合物家族来抵消不断发展的抗药性。基于保守的RNA靶标鉴定和开发一类新的抗菌化合物将创造一个重要的市场机会。治疗目标可能包括肺炎球菌、肠球菌和结核病--特别是它们的抗药性菌株。

The 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.