Supramolecular polymers for targeted protein degradation

用于靶向蛋白质降解的超分子聚合物

• 批准号: 10511617
• 负责人: Tristan Clemons
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF SOUTHERN MISSISSIPPI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10511617
• 关键词: Address; Affinity; Binding; Binding Proteins; Binding Sites; Cells; Clinical; Coupled; Development; Disease; Dose; Drug Design; Drug resistance; Glutathione S-Transferase; Gold; Hydrophobicity; Injury; Intervention; Ligands; Malignant Neoplasms; Methods; Movement; Multi-Drug Resistance; Nanostructures; Neurodegenerative Disorders; Pathologic; Pathway interactions; Peptide Synthesis; Pharmacologic Substance; Play; Polymers; Protac; Protein Inhibition; Proteins; Public Health; Specificity; Surface; System; Techniques; Technology; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Therapeutic Uses; Vision; base; biomaterial compatibility; clinically relevant; comparative efficacy; design; improved; in vitro Model; interest; monomer; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; peptide amphiphiles; peptide drug; premature; protein aggregation; protein degradation; protein function; rational design; recruit; scaffold; self assembly; small molecule; small molecule therapeutics; success; synthetic biology; targeted delivery; tau Proteins; technology development; therapeutic development; ubiquitin-protein ligase

Project Summary Vision: Recent advances in targeted protein degradation strategies such as hydrophobic tagging (HyT) and proteolysis targeting chimeras (PROTACs) have the potential to revolutionize therapeutic development as we know it. This is provided that these strategies can overcome the translational challenges of targeted delivery, improved specificity and cellular internalization. This project outlines two strategies to couple these advanced synthetic biology techniques with novel supramolecular polymers to address these significant hurdles currently facing the field. Supramolecular polymers provide the opportunity to enhance cellular internalization, provide dynamic presentation of protein binding ligands and provide the potential for multivalent, and in turn higher affinity, binding interactions with target proteins. The success of this project could unlock a vast array of new drug targets, previously thought to be undruggable, while circumventing the reliance on small molecule therapeutics and their associated problems with drug resistance. This project will investigate the opportunity of dynamic supramolecular polymers as a strategy to enhance the efficacy of targeted protein degradation therapies The misfolding or misregulation of proteins has been shown to lead to the development of many diseases including neurodegenerative diseases, cancers and fibrotic disorders. Small molecule drugs, designed to inhibit protein function is the current gold standard in the vast majority of clinically-used therapeutic agents available. However, to achieve clinically relevant protein inhibition, greater than 90% target binding is required, resulting in high dosing levels that can result in off-target effects. Further, these approaches are only suitable when the protein target has an active binding site suitable for inhibition. What about the proteins that don’t have an active binding site or contribute to disease through other mechanisms? What if there was another way to not just inhibit but to selectively degrade these aberrant proteins as a therapeutic strategy? We feel this can be achieved with supramolecular polymers designed to achieve targeted protein degradation. To demonstrate the potential and principle of supramolecular polymer targeted protein degraders, we will address the following two specific aims: (1) To synthesize and characterize biocompatible supramolecular polymers capable of self-assembly into nanostructures coupled with achieving degradation through a hydrophobic tagging approach of a protein of interest, (2) Demonstrate efficacy of a multifunctional supramolecular PROTAC polymer capable of self-assembly, cell internalization, targeting and subsequent degradation of a protein of interest.

项目摘要 愿景：疏水标签（HyT）等靶向蛋白质降解策略的最新进展 和蛋白水解靶向嵌合体（PROTAC）具有革命性的治疗潜力， 发展，因为我们知道它。这是提供这些策略可以克服翻译 靶向递送、改进的特异性和细胞内化的挑战。该项目概述了两个 将这些先进的合成生物学技术与新型超分子聚合物结合起来的策略 以解决该领域目前面临的这些重大障碍。超分子聚合物提供了 增强细胞内化的机会，提供蛋白结合配体的动态呈递 并提供了与靶的多价结合相互作用的可能性，进而提供了更高的亲和力 proteins.该项目的成功可能会解锁大量新的药物靶点， 不可用药，同时避免对小分子治疗剂及其相关药物的依赖， 耐药性的问题。 本计画将探讨动态超分子聚合物作为策略的机会 为了增强靶向蛋白降解疗法的功效， 蛋白质的错误折叠或错误调节已被证明会导致许多 疾病，包括神经变性疾病、癌症和纤维变性疾病。小分子药物， 设计用于抑制蛋白质功能的药物是目前绝大多数临床使用的 可用的治疗剂。然而，要实现临床相关蛋白抑制，大于90% 需要靶结合，导致高剂量水平，这可能导致脱靶效应。此外，本发明还 这些方法仅在蛋白质靶具有适合于 抑制作用那些没有活性结合位点或导致疾病的蛋白质呢 通过其他机制？如果有另一种方法不仅能抑制， 降解这些异常蛋白质作为治疗策略我们认为这可以通过 超分子聚合物，旨在实现靶向蛋白质降解。以证明 超分子聚合物靶向蛋白质降解剂的潜力和原理，我们将讨论 具体目标有两个：（1）合成和表征生物相容性超分子聚合物 能够自组装成纳米结构，并通过疏水性 目的蛋白质的标记方法，（2）证明多功能超分子标记的功效， 能够自组装、细胞内化、靶向和随后降解的PROTAC聚合物 一种蛋白质。