Supramolecular polymers for targeted protein degradation

项目摘要 视觉：靶向蛋白质降解策略的最新进展，如疏水标记(HYT) 而针对嵌合体的蛋白水解酶(PROTAC)有可能彻底改变治疗方法 如我们所知的发展。这是假设这些策略可以克服翻译 靶向传递、改进的特异性和细胞内化的挑战。这个项目概述了两个 将这些先进的合成生物学技术与新型超分子聚合物相结合的策略 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，提供蛋白质结合配体的动态呈现 并提供与靶的多价结合作用的可能性，进而提供更高亲和力的结合作用 蛋白质。该项目的成功可能会解锁一系列新的药物靶点，这是之前的想法 不可用药，同时避免对小分子疗法及其相关药物的依赖 抗药性问题。 本项目将研究动态超分子聚合物作为一种策略的机会 提高靶向蛋白质降解疗法的疗效 蛋白质的错误折叠或错误调节已被证明会导致许多 疾病包括神经退行性疾病、癌症和纤维性疾病。小分子药物， 设计抑制蛋白质功能是目前绝大多数临床上使用的黄金标准 可用的治疗剂。然而，要实现临床相关的蛋白质抑制，大于90% 需要靶标结合，导致高剂量水平，可能导致非靶标效应。此外， 这些方法仅适用于当蛋白质靶标具有适合于 抑制力。那些没有活性结合部位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可以抑制，而且可以有选择地 将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 旨在实现蛋白质定向降解的超分子聚合物。要演示 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 以下两个具体目标：(1)合成和表征生物相容性的超分子聚合物 能够自组装成纳米结构，并通过疏水实现降解 目标蛋白质的标记方法，(2)展示多功能超分子的有效性 具有自组装、细胞内化、靶向和后续降解能力的PROTAC聚合物 一种感兴趣的蛋白质。

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.