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泛素-蛋白酶体是人体内降解蛋白质的主要途径,通过该酶体来抑制蛋白质的降解是近年来治疗癌症的新策略,同时还扩大了化学治疗药的靶标。该蛋白酶体调控着人体内非必需或废弃细胞蛋白的降解,这一过程在许多癌症细胞中往往调控紊乱。基于这个靶标,治疗多发性骨髓瘤的二肽硼酸类化合物Bortezomib,在2003年得到了FDA的批准,成为该靶点第一个成功上市的药物。随后一系列具有蛋白酶20S抑制活性的合成小分子化合物或提取的天然化合物进入临床实验。本文主要综述了蛋白酶体的结构、蛋白酶抑制剂的作用机制及其抑制剂的合成与分类。
Ubiquitin-proteasome is the main pathway for protein degradation in the human body. Inhibition of protein degradation by this enzyme is a new strategy to treat cancer in recent years. It also expands the target of chemotherapeutic drugs. The proteasome regulates the degradation of nonessential or disrupted cellular proteins in the human body, a process that often modulates disturbances in many cancer cells. Based on this target, Bortezomib, a dipeptide boric acid compound for the treatment of multiple myeloma, was approved by the FDA in 2003 as the first successful marketed drug for this target. Then a series of synthetic small molecule compounds with protease 20S inhibitory activity or extracted natural compounds into clinical trials. This review summarizes the proteasome structure, the mechanism of action of protease inhibitors and the synthesis and classification of inhibitors.