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尽管强效且具有高度选择性的小分子抑制剂仍在不断得到开发与应用,但这类传统药物并不能直接调控细胞内目标蛋白的含量,难以靶向缺乏配体结合口袋的“难成药”靶点[1-3],且起效剂量较大,长期使用耐药性明显[4-6]。因此,随着研究的不断深入,利用细胞内固有的蛋白降解机制靶向降解特定蛋白的方式,引起了科学界的极大关注,并成为一种颇具前景的治疗手段。
泛素-蛋白酶体系统(UPS)是细胞内降解受损或错误折叠蛋白质的核心机制,参与胞内80%以上蛋白质的降解[7]。其主要过程为:首先,泛素(Ub)与泛素激活酶(E1)形成硫酯键;活化的泛素通过硫酯交换反应被转移至泛素结合酶(E2);随后,泛素连接酶(E3)同时结合“E2-泛素复合物”与靶蛋白,使两者在空间上充分接近,驱动泛素转移至靶蛋白。该过程由ATP供能,多次重复可使底物被泛素链标记,最终被蛋白酶体识别并降解[8-9](图1)。基于UPS的靶向蛋白降解技术中,研究最为成熟的包括PROTAC和分子胶。
除UPS外,在真核生物中还普遍存在另一种降解途径,即溶酶体介导的降解途径。该途径涉及的底物范围十分广泛,包括衰老或受损的细胞器、蛋白质聚集体以及入侵的病原微生物等,与UPS互为补充。溶酶体降解途径主要包括内体-溶酶体途径(ELP)[10]和自噬-溶酶体途径(ALP)[11-12],因此,基于ELP的靶向降解技术主要应用于胞外蛋白和膜蛋白的靶向降解,例如LYTAC;ELP是指细胞通过受体介导的内吞作用将胞外物质或膜蛋白与内体融合,并最终转运至溶酶体中降解的过程(图2A);ALP通常是指在自噬关键蛋白LC3的参与下,通过形成自噬小体将底物包裹,最终与溶酶体融合实现降解的过程(图2B)。基于ALP的靶向降解技术进一步拓展了靶向降解胞内蛋白(包括蛋白聚集体)的技术手段,并成功应用于降解受损细胞器和其它非蛋白生物分子,主要降解技术包括ATTEC、AUTAC和AUTOTAC等。
基于以上两种途径的靶向蛋白降解技术,利用“事件驱动”(event driven)而非“占据驱动”(occupation driven)的作用模式发挥功能,理论上仅需催化量的药物即可发挥较强疗效,在靶向“难成药”靶点、提高选择性、克服耐药、降低毒副作用等方面表现出较大的优势,具有广阔的应用前景。本文综述了近年来兴起的代表性的靶向降解策略,并讨论其优势与局限性。
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