Sequence Specific Inhibition of Protein Translation

蛋白质翻译的序列特异性抑制

• 批准号: 10196539
• 负责人: John S Chorba
• 金额: $ 24.23万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10196539
• 关键词: Active Sites; Address; Affect; Amino Acid Sequence; Amino Acids; Antibiotics; Atherosclerosis; Binding; Biological; Biomedical Research; Cell physiology; Cells; Chemicals; Clinic; Clinical; Code; Codon Nucleotides; Communities; Cysteine; Development; Disease; Economics; Emerging Technologies; Failure; Gene Silencing; Goals; Gold; Human; Kinetics; Knowledge; Mediating; Methods; Molecular; Molecular Evolution; Oral; Peptides; Peptidyltransferase; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Process; Production; Protein Inhibition; Proteins; Research; Ribosomes; Specificity; Structure; System; Technology; Testing; Therapeutic; Therapeutic Studies; Thermodynamics; Translating; Translations; analog; base; biochemical tools; chemical genetics; cost; drug discovery; improved; inhibitor/antagonist; innovation; interest; novel; personalized strategies; prevent; protein aminoacid sequence; small molecule; theories; therapeutic target; tool; translatome

PROJECT SUMMARY/ABSTRACT An inherent challenge in drug discovery is that every target requires its own individualized strategy. Many targets are “undruggable” by small molecules, which, owing to their rapid onset and low cost, are the pharmacologic cornerstone of both clinical therapies and research tools alike. A generalizable solution to inhibit the function of any given protein with a small molecule is therefore a holy grail of biomedical research. A possible solution exists in a recently described small molecule which stalls the translation of a very limited number of protein targets. This class of molecules binds in the ribosome exit tunnel to allosterically alter the peptidyl transferase center and prevent elongation, doing so in a manner that is dependent on the sequence identity of nascent chain. Though this novel mechanism of action is exciting, the off-target effects of the current compounds precludes their use either as therapeutics or as a clean sequence-specific chemical probe. In this proposal, we will directly address whether these compounds can be developed into useful research tools. In Aim 1, we will probe the intrinsic limits of the specificity of this technology, doing so by developing an optimized chemical genetics pair between the known compounds and an evolved target peptide sequence. In Aim 2, we will evaluate whether the maximum efficacy of these compounds can be improved by developing covalent analogs that can target specific cysteine-containing nascent chains. In Aim 3, we will ask whether the structures of the compounds can be tuned to alter the sequence specificity of the nascent chains they target. We will do this via an innovative kinetic target-templated synthetic strategy, which will simultaneously probe the accessible chemical space of the binding pocket with the exit tunnel, while also producing nascent chain specific chemical probes. We anticipate that advances in any one of these Aims would allow this technology to be further developed into a powerful tool: the ability to stop, and then restart, the protein production of any target of interest.

项目摘要/摘要 药物发现中的继承挑战是每个目标都需要自己的个性化策略。许多 小分子的靶标是“不可能的”，由于其快速发作和低成本，它是 临床疗法和研究工具的药理学基石。可抑制的概括解决方案 因此，任何给定蛋白质的蛋白质的功能是生物医学研究的圣杯。一个 可能的解决方案存在于最近描述的小分子中，该分子失速了非常有限的翻译 蛋白质靶标数。这类分子在核糖体出口隧道中结合，以改变 肽基转移酶中心并防止伸长，以依赖序列的方式进行延长 新生链的身份。尽管这种新颖的作用机理令人兴奋，但电流的脱靶影响 化合物排除它们作为治疗或清洁序列特异性化学探针的使用。在这个 提案，我们将直接解决是否可以将这些化合物发展为有用的研究工具。在 AIM 1，我们将通过开发优化的技术来探测该技术特异性的内在限制 已知化合物与进化的靶肽序列之间的化学遗传学对。在AIM 2中，我们 将通过开发共价评估这些化合物的最大效率是否可以提高 可以针对特定含半胱氨酸的新生链的类似物。在AIM 3中，我们将询问是否 可以调整化合物的结构以改变其靶向的新生链的序列特异性。 我们将通过创新的动力学目标合成策略来做到这一点，这将简单地探究 带有出口隧道的装订袋的可访问的化学空间，同时还会产生新生的链条 具体的化学问题。我们预计，这些目标中的任何一个都将使这项技术能够 进一步发展为一个强大的工具：停止，然后重新启动的能力，即任何蛋白质的产生 感兴趣的目标。