Chinese Scientists Uncover the Structural and Biochemical Properties of Core Polymerase Complex from COVID-19 Virus

The outbreak of COVID-19 has developed into a global pandemic affecting almost all countries in the world. As of 1^st June 2020, more than 6,300,000 human infections have been reported worldwide, including over 370,000 deaths, according to the statistics by Johns Hopkins University. Currently, there are no specific drugs or vaccines available for this newly emerging virus.

COVID-19 is caused by a novel coronavirus named Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), which belongs to the family of Coronaviridae, a group of positive-sense RNA virus with a broad host-spectrum. So far, a total of seven human-infecting coronaviruses have been identified.

Among them, SARS-CoV-2 displays the highest similarity in genome sequence to SARS-CoV which emerged in 2002-2003. Both viruses utilize the same host receptor angiotensin-converting enzyme 2 (ACE2) for cell entry and cause respiratory symptoms that may progress to severe pneumonia and lead to death.

However, as compared to SARS-CoV, SARS-CoV-2 shows a much higher transmission efficiency and a lower mortality rate. Most of the infections result in mild symptoms and a substantial number of asymptomatic infection cases have also been reported.

The replication of coronavirus is operated by a set of non-structural proteins (nsps) encoded by its genome, which are initially translated as polyproteins followed by proteolysis cleavage to generate mature viral proteins. These proteins assemble into a multi-subunit polymerase complex to mediate the transcription and replication of viral genome.

Among them, nsp12 is the catalytic subunit with RNA-dependent RNA polymerase (RdRp) activity. The nsp12 itself is capable of conducting polymerase reaction with extremely low efficiency, whereas the presence of nsp7 and nsp8 cofactors remarkably stimulates its polymerase activity. The nsp12-nsp7-nsp8 subcomplex is thus defined as the minimal core components for mediating coronavirus RNA synthesis.

To achieve the complete transcription and replication of viral genome, several other nsp subunits are required to assemble into a holoenzyme complex, including the nsp10, nsp13, nsp14 and nsp16, for which the precise functions for RNA synthesis have not been well understood.

On 30^th May 2020, SHI Yi’s Group at Institute of microbiology, Chinese Academy of Science reported the 3D structure and enzymatic properties of the core polymerase complex from COVID-19 virus in Cell Reports.

This complex consists of the nsp12 catalytic subunit bound with a copy of nsp7 and two asymmetric nsp8 cofactors. The structure highly resembles the counterpart of SARS-CoV with conserved motifs for all viral RNA-dependent RNA polymerase, and suggests the mechanism for catalysis activation by cofactors. These findings provide important basis for developing antiviral drugs that inhibit RNA synthesis by targeting the viral polymerase complex.