LARGE RIBOSOMAL SUBUNIT BOUND TO NEWLY DESIGNED INHIBITORS OF PROTEIN SYNTHESIS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 在Rib-X制药公司，我们采用基于结构的设计策略来寻找针对核糖体的新型抗生素化学类别。医学上迫切需要绕过细菌中已有的抗生素耐药性机制的新药，许多常见的药物类别，如青霉素和大环内酯类，在世界许多地区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，但那些与翻译装置结合的抗生素构成了大多数用途。翻译的核心是核糖体，这是一种2.5MDa的大分子复合体，在所有生物体中唯一催化蛋白质的合成，一直是许多天然和合成抗生素的靶标。 利用我们对重要药物-RNA结合作用的不断提高的知识，我们目前正在基于不同的新型分子支架设计更多的下一代抗生素。为此，我们建议使用我们的晶体与室内合成的新型蛋白质翻译抑制剂结合起来，积累更多的结构信息。我们从我们的H.marismortui 50S晶体中获得的结构信息将对我们当前计划中具有日益改进的药物性质的化合物的后续设计至关重要。 此外，50s亚基的巨大尺寸和翻译装置中固有的无数大分子相互作用，提供了许多干扰翻译的小分子结合位置。这些区域中有相当一部分位于肽基转移酶中心的远端，在原细菌和真细菌王国之间没有得到很好的保存。因此，我们还建议从革兰氏阳性细菌中确定与50S核糖体亚单位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原始核糖体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置上使用我们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. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.