Potential treatment of COVID-19 by inhibitors of human dihydroorotate dehydrogenase
Yechun Xu, Hualiang Jiang
Abstract
The ongoing pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), referred to as coronavirus disease 2019 , has caused over 13 million infections and over 560,000 deaths worldwide (https://www. who.int/emergencies/diseases/novel-coronavirus-2019/sit uation-reports), posing a significant threat to globally public health and economics. At present, no efficacious antiviral drugs and vaccines have been approved for the prophylaxis or treatment of COVID-19. Tremendous efforts have been made to develop drug and vaccine against SARS-CoV-2. The main protease (Mpro, also called 3CLpro) is an attractive drug target among coronaviruses, and several potent inhibitors of the SARS-CoV-2 3CLpro together with their crystal structures in complex with the protease have been reported While the viral RNA-dependent RNA polymerases (RdRp) are well-known broad-spectrum antiviral drug targets, the cryo-electron microscopy structures of the SARS-CoV-2 RdRp and its complex with remdesivir, a promising antiviral candidate developed by Gilead Sciences, validated the efficient inhibition of the viral RNA replication by remdesivir and provided a rational template for drug design to combat SARS-CoV-2 infections In addition, the trimeric spike protein on the surface of SARS-CoV-2 plays a pivotal role during the viral entry by binding to the peptidase domain of angiotensin-converting enzyme 2 (ACE2), a host cell receptor It has been revealed that not only the receptor binding domain which is recognized by ACE2 but also the N-terminal domain of the SARS-CoV-2 spike protein is targeting sites for therapeutic monoclonal antibodies Accordingly, both the inhibitors of 3CLpro or RdRp and the antibodies targeting the spike protein provide potential candidates for development of the direct-acting antiviral (DAA) drugs for the treatment of COVID-19.