LARGE RIBOSOMAL SUBUNIT BOUND TO NEWLY DESIGNED INHIBITORS OF PROTEIN SYNTHESIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 在Rib-X制药公司，我们采用基于结构的设计策略来寻找靶向核糖体的新型化学抗生素。对规避细菌中已建立的抗生素耐药性机制的新药的医疗需求是迫切的，许多常见的药物类别如青霉素和大环内酯类在世界许多地方具有高水平的社区耐药性。 尽管许多抗生素针对细菌生命周期的其他方面，但与翻译装置结合的抗生素占大多数。 翻译的核心是核糖体，一种2.5MDa的大分子复合物，独特地催化所有生物体中的蛋白质合成，这是许多天然和合成抗生素的目标。 利用我们对重要的药物-RNA结合相互作用的不断改进的知识，我们目前正在寻求基于不同的新型分子支架设计额外的下一代抗生素。 因此，我们建议使用我们的H晶体来积累更多的结构信息。marismortui 50 S与内部合成的新型蛋白质翻译抑制剂结合。 我们从H. marismortui 50 S晶体将是必不可少的后续设计的化合物与日益改善的药物一样的性质在我们目前的计划。 此外，50 S亚基的绝对大小和翻译装置中固有的无数大分子相互作用提供了许多会干扰翻译的小分子结合位置。 大量的这些区域是远端的肽基转移酶中心，并没有很好地保守之间的古细菌和真细菌界。 因此，我们还建议确定从革兰氏阳性菌的50 S核糖体亚基结合的几种抑制剂的晶体结构。 这些结构将使我们能够利用古细菌和真细菌核糖体之间的分子差异，并在这些基本但不太保守的位点上采用我们的基于迭代结构的药物设计方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. At Rib-X Pharmaceuticals, Inc., we employ a structure-based design strategy to find novel chemical classes of antibiotics that target the ribosome. The medical need for new drugs that circumvent established antibiotic resistance mechanisms in bacteria is dire, with many common drug classes such as penicillins and macrolides having high levels of community resistance in many parts of the world. Though many antibiotics target other aspects of the bacterial life cycle, those that bind to the translational apparatus constitute a majority of use. The central player in translation is the ribosome, a 2.5MDa macromolecular complex that uniquely catalyzes the synthesis of proteins in all organisms that has been the target of many antibiotics, both natural and synthetic. Using our constantly improving knowledge of important drug-RNA binding interactions, we are currently pursuing the design of additional next generation antibiotics based on different novel molecular scaffolds. For such, we propose to accumulate more structural information using our crystals of H. marismortui 50S bound to novel inhibitors of protein translation synthesized in house. The structural information we obtain from our H. marismortui 50S crystals will be essential for the subsequent design of compounds with increasingly improved drug-like properties within our current programs. Furthermore, the sheer size of the 50S subunit and the myriad of macro-molecular interactions inherent in the translational apparatus, affords many small molecule binding locations that would interfere with translation. A substantial number of these regions are distal to the peptidyl-transferase center and are not well conserved between the archeal and eubacterial kingdoms. Therefore, we also propose to determine the crystal structures of several inhibitors bound to the 50S ribosomal subunit from a Gram-positive bacterium. These structures will allow us to the exploit molecular differences between archeal and eubacterial ribosome, and employ our iterative structure based drug design methodology on these essential yet less well conserved sites.