Chen Xin, Chou Chi-Yuan, Chang Gu-Gang
Division of Biotechnology and Pharmaceutical Research, National Health Research Institute, Miaoli, Taiwan.
Antivir Chem Chemother. 2009;19(4):151-6. doi: 10.1177/095632020901900402.
In the search for effective therapeutics against severe acute respiratory syndrome (SARS), 6-mercaptopurine (6MP) and 6-thioguanine (6TG) were found to be specific inhibitors for the SARS-coronavirus (CoV) papain-like protease (PLpro), a cysteine protease with deubiquitinating and deISGylating activity. 6MP and 6TG have long been used in cancer chemotherapy for treatment of acute lymphoblastic or myeloblastic leukaemia. Development and optimization of 6MP and 6TG will not only be important for antiviral studies, but also for further elucidating the biological functions of cellular deubiquitinating enzymes (DUBs) and deISGylating enzymes. So far, several crystal structures of cellular DUBs have been solved. Structure comparison has been carried out to search for DUBs with a similar structure to that of PLpro, and we have tried to dock 6MP and 6TG into these DUBs to investigate the potential use of 6MP and 6TG as cellular DUB inhibitors. The best docking score and binding energy for 6MP and 6TG is against ubiquitin-specific protease (USP)14, suggesting that 6MP and 6TG are potential inhibitors of USP14. Finding new usages for old drugs will speed up the process of drug discovery and substantially reduce the cost of drug development.
在寻找针对严重急性呼吸综合征（SARS）的有效治疗方法的过程中，发现6-巯基嘌呤（6MP）和6-硫鸟嘌呤（6TG）是严重急性呼吸综合征冠状病毒（SARS-CoV）木瓜样蛋白酶（PLpro）的特异性抑制剂，PLpro是一种具有去泛素化和去ISGylation活性的半胱氨酸蛋白酶。6MP和6TG长期以来一直用于癌症化疗，治疗急性淋巴细胞白血病或急性髓细胞白血病。6MP和6TG的开发和优化不仅对抗病毒研究很重要，而且对于进一步阐明细胞去泛素化酶（DUBs）和去ISGylation酶的生物学功能也很重要。到目前为止，已经解析了几种细胞DUBs的晶体结构。已经进行了结构比较，以寻找与PLpro结构相似的DUBs，并且我们试图将6MP和6TG对接至这些DUBs中，以研究6MP和6TG作为细胞DUB抑制剂的潜在用途。6MP和6TG的最佳对接分数和结合能是针对泛素特异性蛋白酶（USP）14，这表明6MP和6TG是USP14的潜在抑制剂。为旧药寻找新用途将加速药物发现过程，并大幅降低药物开发成本。
