Supramolecular polymers for targeted protein degradation

用于靶向蛋白质降解的超分子聚合物

基本信息

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
项目类别：
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

项目摘要

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.

项目概要愿景：疏水标记 (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）有可能彻底改变治疗方法前提是这些策略能够克服转化。该项目概述了靶向递送、提高特异性和细胞内化的两个挑战。将这些先进的合成生物学技术与新型超分子聚合物相结合的策略为了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解决方案。有机会增强细胞内化，提供蛋白质结合配体的动态呈现并提供与靶标进行多价结合相互作用的潜力，进而提供更高的亲和力此前认为，该项目的成功可以解锁大量新的药物靶点。不可成药，同时避免对小分子疗法及其相关药物的依赖耐药性问题。该项目将研究动态超分子聚合物作为策略的机会增强靶向蛋白质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的发展疾病包括神经退行性疾病、癌症和纤维化疾病，旨在抑制蛋白质功能是目前绝大多数临床使用的金标准然而，现有的治疗药物可以实现临床相关的蛋白质抑制率大于90%。需要靶标结合，导致高剂量水平可能导致脱靶效应。这些方法仅适用于当蛋白质靶标具有适合的活性结合位点时那些没有活性结合位点或导致疾病的蛋白质呢？如果有另一种方法不仅可以抑制，而且可以选择性地抑制呢？降解这些异常蛋白质作为一种治疗策略？我们认为这可以通过以下方式实现：旨在实现目标蛋白质降解的超分子聚合物。超分子聚合物靶向蛋白质降解剂的潜力和原理，我们将讨论遵循两个具体目标：（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，并通过疏水性实现降解感兴趣的蛋白质的标记方法，(2) 展示多功能超分子的功效 PROTAC 聚合物能够自组装、细胞内化、靶向和随后的降解感兴趣的蛋白质。