A team of Chinese scientists has reported the high-resolution cryo-EM structure of RNA and remdesivir bound RNA-Dependent RNA Polymerase(RdRp) complex from SARS-CoV-2.

The research, published online in Science on May 1, was conducted by Prof. XU Huaqiang and Prof. XU Yechun from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences (CAS), Prof. ZHANG Yan from the Zhejiang University School of Medicine, Prof. ZHANG Shuyang from Peking Union Medical College and Chinese Academy of Medical Sciences, and their collaborators.

Since the outbreak of COVID-19, it has spread around the world, causing a huge disaster to all mankind. Many countries around the world still facing huge challenges to fight SARS-CoV-2, and it is very urgent to find an effective treatment.

The SARS-CoV-2 is a positive-strand RNA virus that mainly infects human cells through the mucosal system. The massive replication of the virus requires the rapid synthesis of its genetic RNA. This process is mediated by a multi-subunit replication transcription complex composed of multiple non-structural proteins (nsp) of the virus. The core element is the RdRp complex, which is the core component of coronavirus replication. Numerous nucleoside drugs currently under clinical testing, including Remdesivir, targeting RdRp. Remdesivir is a prodrug form that will be metabolized into the active product in the form of triphosphate in the body to cause the termination of the viral RNA chain extensio.

In order to elaborate the fine anti-viral mechanism of nucleoside drugs, after 46 days of hard work, the team successfully reported the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo form at 2.8 ？ resolution or in complex with a template-primer RNA and Remdesivir at 2.5 ？ resolution.The overall conformation of the complex structure is very similar to that of the apo form, only a certain conformational change in some subdomains.

Comprehensive analysis shows that the SARS-CoV-2 RdRp complex is a very efficient enzyme. During RNA extension, the conformational change is small, which also explains the high contagious ability of the SARS-CoV-2; RdRp complex recognizes RNA but not DNA , in a way of sequence independent binding; the complex structure explains how Remdesivir enters the replication active site and covalently inserts into the viral genome, thereby inhibiting virus replication; The residues involved in RNA binding as well as residues comprising the catalytic active site are highly conserved among most RNA viruses including polio virus, hepatitis C virus, and influenza virus, etc. , showing the conservative mechanism of RdRp complex during gene replication, and suggesting it may be possible to develop broad spectrum antiviral inhibitors The structures provide a structural basis for the urgent development of potential antiviral drugs, helps to study potential binding patterns, and provides theoretical support for the design of more powerful, efficient and specific anti-SARS-CoV-2 drugs.