How Remdesivir Blocks SARS-CoV-2 Replication

Chinese scientists have uncovered the structural basis for SARS-CoV-2 inhibition by Remdesivir.

AsianScientist (May 20, 2020) – In a study published in Science, researchers report the high-resolution structure of Remdesivir-bound RNA replicase complex from SARS-CoV-2, the infective virus of COVID-19. These results could be used to design more powerful and specific drugs for COVID-19.

COVID-19 has spread rapidly around the world and is an ongoing humanitarian crisis. Many countries are now facing tremendous challenges in the fight against SARS-CoV-2, making finding an effective treatment extremely urgent.

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 of the virus. The core element is the replicase complex, which is required for coronavirus replication. Numerous nucleoside drugs targeting replicase are currently under clinical testing, including Remdesivir, a drug originally developed against Ebola.

In the present study, a team led by Professors Xu Huaqiang and Xu Yechun from the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Professor Zhang Yan from the Zhejiang University and Professor Zhang Shuyang from Peking Union Medical College and Chinese Academy of Medical Sciences, have used cryogenic electron microscopy (cryo EM) to understand how Remdesivir binds to the replicase complex.

The researchers compared the cryo EM structure of the SARS-CoV-2 replicase both in the apo form at 2.8 Å resolution and in complex with a template-primer RNA and Remdesivir at 2.5 Å resolution. The overall conformation of the complex structure is very similar to that of the apo form, with the identical structures at the core catalytic active site.

Comprehensive 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 also explains the highly contagious nature of SARS-CoV-2. The structure of the complex also explained how Remdesivir enters the replication active site and covalently links with the viral genome, thereby inhibiting virus replication.

The residues involved in RNA binding as well as those comprising the catalytic active site are highly conserved among RNA viruses. This shows that the mechanism of gene replication could be a possible target of future broad spectrum antiviral inhibitors.

The structures described in this study reveal potential binding patterns that offer theoretical support for the design of drugs against SARS-CoV-2. In this way, they provide a basis for the design of the antiviral drugs, which are so urgently needed to fight the COVID-19 crisis.

The article can be found at: Yin et al. (2020) Structural Basis for Inhibition of the RNA-dependent RNA Polymerase from SARS-CoV-2 by Remdesivir.


Source: Chinese Academy of Sciences; Photo: Shutterstock.
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