Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin–Proteasome system,European Journal of Medicinal Chemistry

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Potential of the nanoplatform and PROTAC interface to achieve targeted protein degradation through the Ubiquitin–Proteasome system
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2024-02-01 , DOI: 10.1016/j.ejmech.2024.116168
Hanshu Xie ₁ , Chao Zhang ₁

Affiliation

In eukaryotic cells, the ubiquitin–proteasome system (UPS) plays a crucial role in selectively breaking down specific proteins. The ability of the UPS to target proteins effectively and expedite their removal has significantly contributed to the evolution of UPS-based targeted protein degradation (TPD) strategies. In particular, proteolysis targeting chimeras (PROTACs) are an immensely promising tool due to their high efficiency, extensive target range, and negligible drug resistance. This breakthrough has overcome the limitations posed by traditionally "non-druggable" proteins. However, their high molecular weight and constrained solubility impede the delivery of PROTACs. Fortunately, the field of nanomedicine has experienced significant growth, enabling the delivery of PROTACs through nanoscale drug-delivery systems, which effectively improves the stability, solubility, drug distribution, tissue-specific accumulation, and stimulus-responsive release of PROTACs. This article reviews the mechanism of action attributed to PROTACs and their potential implications for clinical applications. Moreover, we present strategies involving nanoplatforms for the effective delivery of PROTACs and evaluate recent advances in targeting nanoplatforms to the UPS. Ultimately, an assessment is conducted to determine the feasibility of utilizing PROTACs and nanoplatforms for UPS-based TPD. The primary aim of this review is to provide innovative, reliable solutions to overcome the current challenges obstructing the effective use of PROTACs in the management of cancer, neurodegenerative diseases, and metabolic syndrome. Therefore, this is a promising technology for improving the treatment status of major diseases.

中文翻译：

纳米平台和 PROTAC 接口通过泛素-蛋白酶体系统实现靶向蛋白质降解的潜力

在真核细胞中，泛素-蛋白酶体系统（UPS）在选择性分解特定蛋白质方面发挥着至关重要的作用。 UPS 有效靶向蛋白质并加速其去除的能力极大地促进了基于 UPS 的靶向蛋白质降解 (TPD) 策略的发展。特别是，蛋白水解靶向嵌合体（PROTAC）因其高效、广泛的靶标范围和可忽略不计的耐药性而成为一种非常有前途的工具。这一突破克服了传统上“非成药”蛋白质所带来的限制。然而，它们的高分子量和有限的溶解度阻碍了 PROTAC 的递送。幸运的是，纳米医学领域经历了显着的发展，使得通过纳米级药物递送系统来递送PROTACs成为可能，这有效地改善了PROTACs的稳定性、溶解度、药物分布、组织特异性积累和刺激响应性释放。本文回顾了 PROTAC 的作用机制及其对临床应用的潜在影响。此外，我们提出了涉及有效递送 PROTAC 的纳米平台的策略，并评估了针对 UPS 的纳米平台的最新进展。最终，进行评估以确定利用 PROTAC 和纳米平台进行基于 UPS 的 TPD 的可行性。本次综述的主要目的是提供创新、可靠的解决方案，以克服当前阻碍 PROTAC 在癌症、神经退行性疾病和代谢综合征治疗中有效使用的挑战。因此，这是一项有前途的改善重大疾病治疗现状的技术。

更新日期：2024-02-01

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