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Scientists Uncover Mechanism of SARS-CoV-2 Inhibition by Remdesivir

High-resolution cryo-EM structures of Remdesivir-bound SARS-CoV-2 have been imaged, providing mechanism insights and facilitating drug design efforts to combat the virus.

SARS-CoV-2, the virus causing the COVID-19 pandemic, is closely related to the more familiar severe acute respiratory syndrome coronavirus (SARS-CoV). Possibly due to stronger binding affinity of the virus spike protein for the host receptor, SARS-CoV-2 has much higher incidence of human-to-human transmission, resulting in infection worldwide.

Its replication is mediated by a complex known as RNA-dependent RNA polymerase (RdRp), a target of the antiviral drug Remdesivir. While the structure of RdRp is known, the drug discovery effort is hampered because there is no structure of the SARS-CoV-2 RdRp in complex with an RNA template or with nucleotide inhibitors. Scientists from China have now corrected that fact.

In a recently published paper in Science, the researchers report the cryo-EM structure of the SARS-CoV-2 RdRp either in the apo form at 2.8 Å resolution or in complex with a 50-base template-primer RNA and Remdesivir at 2.5 Å resolution. The complex structure reveals that the partial double-stranded RNA template is inserted into the central channel of the RdRp where Remdesivir is covalently incorporated into the primer strand at the first replicated base pair, which terminates chain elongation.

Further analysis of the structures showed that the SARS-CoV-2 replicase complex is a very efficient enzyme. During RNA extension, conformational change is small, which explains its highly contagious nature. The residues involved in RNA binding as well as those comprising the catalytic active site are highly conserved among most RNA viruses. This shows the conservative mechanism of the replicase complex during gene replication and suggests it may be possible to develop broad spectrum antiviral inhibitors. [APBN]