RNA: New Antimicrobial Strategies

RNA：新的抗菌策略

• 批准号: 8558083
• 负责人: Adrian Ferre-D'Amare
• 金额: $ 93.33万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8558083
• 关键词: Adopted; Affinity; Alternative Splicing; Antibiotic Resistance; Antibiotics; Bacillus (bacterium); Binding; Biochemical; Catalytic RNA; Cell Wall; Clostridium; Coenzymes; Complex; Development; Evolution; Genetic Transcription; Genus staphylococcus; Laboratories; Lead; Ligands; Listeria; Location; Metabolic Pathway; Organism; Program Development; Public Health; RNA; Regulator Genes; Research; Screening procedure; Signal Pathway; Specificity; Streptococcus; Structure; Study Subject; Synthesis Chemistry; Thiamine Pyrophosphate; Translations; Work; analog; antimicrobial; base; design; functional group; glucosamine 6-phosphate; insight; interest; mRNA Decay; novel; novel therapeutics; pathogenic bacteria; three dimensional structure; tool

In the past year, efforts have centered on the glmS ribozyme-riboswitch and the thiamine pyrophosphate (TPP) riboswitch. The former is a catalytic RNA that controls synthesis of the bacterial cell wall in Gram-positive organisms. Previous crystallographic and biochemical work in our laboratory has demonstrated that glucosamine-6-phosphate (GlcN6P) functions as a coenzyme of the RNA. We have developed a synthetic chemistry program for the development of novel, unnatural GlcN6P analogs with better stability and potency than the natural metabolite. The TPP riboswitch is widely distributed phylogenetically. Previously, our collaborator Dr. Abell and coworkers have carried out a fragment-based screen against this riboswitch and found a number of small organic molecules that bind with high specificity, albeit low affinity, to the RNA. Fragment-based screening is predicated on being able to elucidate the binding location of the low affinity fragments so that they can be elaborated into high affinity binders. Crystallographic work underway in our laboratory has confirmed the specificity of binding of a number of fragments, and elaboration of these into more potent ligands for the TPP riboswitch is underway.

在过去的一年里，研究工作集中在glmS核酶核糖开关和焦磷酸硫胺素（TPP）核糖开关上。 前者是一种催化 RNA，控制革兰氏阳性生物体中细菌细胞壁的合成。 我们实验室之前的晶体学和生物化学工作已经证明，6-磷酸氨基葡萄糖 (GlcN6P) 可以作为 RNA 的辅酶。 我们开发了一个合成化学计划，用于开发新型非天然 GlcN6P 类似物，其稳定性和效力比天然代谢物更好。 TPP核糖开关在系统发育上分布广泛。 此前，我们的合作者 Abell 博士和同事对这种核糖开关进行了基于片段的筛选，发现了许多小有机分子，它们与 RNA 具有高特异性（尽管亲和力低）结合。 基于片段的筛选的前提是能够阐明低亲和力片段的结合位置，以便将它们精心制作成高亲和力结合物。 我们实验室正在进行的晶体学工作已经证实了许多片段结合的特异性，并且正在将这些片段细化为 TPP 核糖开关的更有效的配体。