In a paper published in the journal Science, a team of researchers from China reports the structure of the antiviral drug remdesivir bound to both a molecule of RNA and to the SARS-CoV-2 viral polymerase. The study illuminates the mechanism that remdesivir uses to interrupt RNA replication and shut down viral reproduction — and may inform efforts to develop new and more potent therapies that employ a similar mechanism.
Cryo-EM structure of the remdesivir and RNA bound RdRp complex: (A and B) two views of cryo-EM map (A) and structure (B) of the nsp12-nsp7-nsp8 in complex with template-primer RNA and remdesivir; (C) surface view of the RdRp active site with the electrostatic potential from red (negative) to blue (positive); for clarity, residues 410-442, 834-919 of nsp12 and nsp8 are excluded from the figure; the covalently bound remdesivir in the monophosphate form and the product, pyrophosphate, are shown; the active site is emphasized with a yellow dashed circle; the template groove, the entrance for NTP and the elongation direction are annotated with different colored arrows; (D) a close view of the RdRp active site, showing the covalently bound RMP, pyrophosphate, and magnesium ions; key residues and bases that interact with remdesivir are shown; (E and F) superposition of the conserved RdRp motifs (A to G) of the RNA bound complex with the apo structure colored in gray, with a close view at the active site (E) and at the exit of the template and primer strand (F). Image credit: Yi et al, doi: 10.1126/science.abc1560.
The pandemic of COVID-19 caused by the SARS-CoV-2 coronavirus has become a global crisis.
The replication of SARS-CoV-2 requires the viral RNA-dependent RNA polymerase (RdRp), a target of the antiviral drug remdesivir.
Prior work had reported the structure of RdRp using cryo-electron microscopy (cryo-EM).
Dr. Wanchao Yin from the Shanghai Institute of Materia Medica and the Zhejiang University School of Medicine and colleagues took this further by again imaging RdRp, which consists of four subunits (nsp12, nsp7, and two units of nsp8), using cryo-EM at 2.8 angstrom resolution.
The researchers then imaged a complex of the polymerase bound to both an RNA template and to a molecule of remdesivir, using cryo-EM at 2.5 angstrom resolution.
In its active form, remdesivir mimics the structure of adenosine, a nucleoside that is incorporated into RNA during replication.
When the drug, instead of a nucleoside, is added to a new RNA molecule it blocks further synthesis of viral RNA.
The detailed cryo-EM structural information enabled the team to pinpoint the precise residues of the polymerase that interact with both the RNA template and remdesivir.
These insights, in turn, will inform efforts to design more effective therapies that also mimic nucleosides to disrupt viral replication.
They also may lead to better understanding of existing nucleoside mimic drugs such as EIDD-2801, ribavirin, galidesivir, and favipiravir.
“Our observations provide a rational basis to design even more potent inhibitors to combat the vicious infection of SARS-CoV-2,” they said.
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Wanchao Yi et al. Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir. Science, published online May 1, 2020; doi: 10.1126/science.abc1560
Source link: https://www.sci.news/medicine/remdesivir-mechanism-action-sars-cov-2-08388.html
