Abstract：
The development and application of traditional drugs represented by small molecule chemical drugs and biological agents, especially inhibitors, have become the mainstream drug development. In recent years, targeted protein degradation (TPD) technology has become one of the most promising methods to remove specific disease-related proteins using cell self-destruction mechanisms. Many different TPD strategies are emerging based on the ubiquitin-proteasome system (UPS) and the autophagy-lysosomal pathway (ALP), including but not limited to proteolysis-targeting chimeras (PROTAC), molecular glues (MG), lysosome targeting chimeras (LYTAC), chaperone-mediated autophagy (CMA)-targeting chimeras, autophagy-targeting chimera (AUTAC), autophagosome-tethering compound (ATTEC), and autophagy-targeting chimera (AUTOTAC). The advent of targeted degradation technology can change most protein targets in human cells from undruggable to druggable, greatly expanding the therapeutic prospect of refractory diseases such as metabolic syndrome. Here, we summarize the latest progress of major TPD technologies, especially in metabolic syndrome and look forward to providing new insights for drug discovery.
摘要：
以小分子化学药物和生物制剂为代表的传统药物的开发和应用，尤其是抑制剂,已成为药物开发的主流。近年来,靶向蛋白降解（TPD）技术已成为利用细胞自我破坏机制去除特定疾病相关蛋白的最有前途的方法之一。基于泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径（ALP），正在出现许多不同的TPD策略。包括但不限于蛋白水解靶向嵌合体（PROTAC），分子胶（MG），溶酶体靶向嵌合体(LYTAC)，伴侣介导的自噬（CMA）靶向嵌合体，自噬靶向嵌合体(AUTAC),自噬体系链化合物（ATTEC），和自噬靶向嵌合体(AUTOTAC)。靶向降解技术的出现可以改变人类细胞中的大多数蛋白质靶标，从不可药用到可药用，大大拓展了代谢综合征等难治性疾病的治疗前景。这里,我们总结了主要TPD技术的最新进展，特别是在代谢综合征中，并期待为药物发现提供新的见解。
