Scientists chart weak spots in coronavirus protein that antiviral drugs can target

Alan Boyle
A cryo-EM map of a portion of the novel coronavirus’ protein structure shows several substructures, including a hairpin-shaped protein that hadn’t been identified previously. (Gao et al. / Science / AAAS)

Chinese researchers say they’ve mapped out a key protein structure in the virus that causes COVID-19, including the likeliest target for the antiviral drug remdesivir.

What’s more, they say that same atomic-scale target, known as nsp12, could be attacked by other types of antiviral drugs.

“This target … could support the development of a cocktail of anti-coronavirus treatments that potentially can be used for the discovery of broad-spectrum antivirals,” the researchers write in a paper published today by the journal Science.

The report boost confidence that remdesivir, which is currently going through accelerated clinical trials at the University of Washington and other research centers across the country, will prove effective for treating COVID-19 patients. It also illustrates how a detailed picture of the coronavirus’ inner workings — provided through a technology known as cryogenic electron microscopy, or cryo-EM — can point to additional strategies for beating the virus.

“To beat COVID-19, its replication and transcription machinery has to be taken down. To do that well, we need to know its high-resolution 3-D structure,” Eric Topol, director of the Scripps Research Translational Institute, said in a tweet. “Today we’ve got the cryo-EM.”

The cryo-EM suggests that remdesivir gums up the works for nsp12, a protein substructure that acts as a “copy machine” for the coronavirus. The newly published protein map includes a hairpin-like structure that hadn’t been identified previously.

Remdesivir has been effective against other types of coronavirus, and the Science paper supports the view that it should also be effective against SARS-CoV-2, the virus responsible for the current global pandemic.

Other existing antiviral drugs, including favipiravir, may well work in the same way, the researchers say.

Still more drug candidates target other parts of the virus, such as the spike-shaped protein that the coronavirus uses like a key to gain entry into human cells. A cryo-EM map of the protein was published less than two months ago, and since then researchers around the world have been looking for ways to blunt the spike.

Last week, scientists at the Scripps Research Institute published a paper in Science showing how a previously known antibody called CR3022 can be used against the spike. And at UW’s Institute for Protein Design, researchers worked with the players of a protein-folding video game called Foldit to identify 99 synthetic proteins with the most potential to counter coronavirus.

Cryo-EM maps can also guide the development of vaccines, which offer the best long-term hope for stopping the virus in its tracks.

Yan Gao of Tsinghua University and ShanghaiTech University is the principal author of the paper published by Science, “Structure of the RNA-Dependent RNA Polymerase From COVID-19 Virus,” and the corresponding authors are Quan Wang, Zhiyong Lou and Zihe Rao. Twenty-four other researchers are co-authors. A preprint version of the paper was posted on the BioRxiv server last month.

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