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.

项目概要/摘要 药物发现的一个固有挑战是每个目标都需要自己的个性化策略。 小分子对目标是“不可成药的”，由于起效快且成本低，小分子是 临床治疗和研究工具的药理学基石，一种通用的抑制解决方案。 因此，任何特定蛋白质与小分子的功能都是生物医学研究的圣杯。 可能的解决方案存在于最近描述的一种小分子中，它阻止了非常有限的翻译 此类分子结合在核糖体出口通道中以变构改变 肽基转移酶中心并防止延伸，其方式取决于序列 尽管这种新颖的作用机制令人兴奋，但当前的脱靶效应。 化合物妨碍了它们作为治疗剂或作为清洁的序列特异性化学探针的用途。 在提案中，我们将直接讨论这些化合物是否可以开发成有用的研究工具。 目标 1，我们将通过开发优化的技术来探索该技术特异性的内在限制 在目标 2 中，我们对已知化合物和进化的目标肽序列进行化学遗传学配对。 将评估是否可以通过开发共价键来提高这些化合物的最大功效 在目标 3 中，我们会问是否可以靶向特定的含半胱氨酸的新生链。 可以调整化合物的结构以改变它们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模板合成策略来做到这一点，该策略将同时探测 结合口袋与出口隧道的化学空间，同时还产生新生链 我们预计这些目标中任何一个的进步都将使这项技术成为可能。 进一步发展成为一个强大的工具：能够停止然后重新启动任何蛋白质的生产 兴趣目标。