Thiopurine Analogue Inhibitors of Severe Acute Respiratory Syndrome-Coronavirus Papain-Like Protease, a Deubiquitinating and deISGylating Enzyme

• Published in: Antiviral chemistry & chemotherapy Vol. 19; no. 4; pp. 151 - 156
• Main Authors: Chen, Xin, Chou, Chi-Yuan, Chang, Gu-Gang
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.02.2009; International Medical Press; Sage Publications Ltd
• Subjects: 6-Mercaptopurine; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Chemotherapy; Coronaviridae; Coronaviruses; Cysteine Endopeptidases - chemistry; Cysteine proteinase; Drug development; Enzymes; Human viral diseases; Humans; Infectious diseases; Leukemia; Medical sciences; Mercaptopurine - chemistry; Mercaptopurine - pharmacology; Mercaptopurine - therapeutic use; Papain; Pharmacology. Drug treatments; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protease Inhibitors - therapeutic use; SARS Virus - enzymology; Severe acute respiratory syndrome; Severe Acute Respiratory Syndrome - drug therapy; Severe Acute Respiratory Syndrome - virology; Thioguanine; Thioguanine - chemistry; Thioguanine - pharmacology; Thioguanine - therapeutic use; Ubiquitin; Ubiquitin-specific proteinase; Viral diseases; Viral diseases of the respiratory system and ent viral diseases; Viral Proteins - antagonists & inhibitors; Viral Proteins - chemistry; Ubiquitin; Lung disease; Pharmaceutical technology; Respiratory disease; Enzyme; Cysteine endopeptidases; Severe acute respiratory syndrome; Thiopurine derivatives; Papain; Infection; Virus; Peptidases; Coronavirus; Viral disease; Hydrolases; Inhibitor; Coronaviridae; Mechanism of action; Nidovirales
• ISSN: 2040-2066; 0956-3202; 2040-2066
• 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 anti-viral 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.