RNA: New Antimicrobial Strategies

RNA：新的抗菌策略

• 批准号: 8939899
• 负责人: Adrian Ferre-D'Amare
• 金额: $ 70.5万
• 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/8939899
• 关键词: Adopted; Affinity; Agonist; Alternative Splicing; Antibiotic Resistance; Antibiotics; Bacillus (bacterium); Binding; Biochemical; Catalytic RNA; Clostridium; Complex; Development; Evolution; Genetic Transcription; Genus staphylococcus; Laboratories; Lead; Ligand Binding; Ligands; Listeria; Location; Metabolic Pathway; Methodology; Molecular; Public Health; Publications; RNA; Regulator Genes; Research; Roentgen Rays; Signal Pathway; Solutions; Specificity; Streptococcus; Structure; Study Subject; Translations; Work; antimicrobial; base; design; functional group; insight; interest; mRNA Decay; novel; novel therapeutics; pathogenic bacteria; response; screening; three dimensional structure; tool

In the past year, two lines of research yielded publications. First, we continue to develop methodology for screening new agonists, antagonists and allosteric effectors of biologically important RNAs. The continued development of solution methodology that can readily detect the molecular response of RNAs to ligand binding, such as small-angle X-ray screening remains a priority. 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 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.

去年，两项研究发表了论文。 首先，我们继续开发筛选具有重要生物学意义的RNA的新激动剂、拮抗剂和变构效应子的方法。 持续开发能够轻松检测 RNA 对配体结合的分子反应的解决方案方法（例如小角度 X 射线筛选）仍然是一个优先事项。 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。