Crystal Structure of Key SARS-CoV-2 Enzyme Unraveled – Paving the Way for New COVID Antivirals



A group of Mount Sinai researchers have created a high-resolution crystal structure of an enzyme required for SARS-CoV-2, the virus that causes COVID-19, to survive. The discovery may aid in the development of critically needed new antivirals to fight coronaviruses both now and in the future.

The RNA methyltransferase domain, a crucial component of the enzyme known as nsp14, is present. The three-dimensional crystal structure of this region has defied prior attempts by the scientific community to characterize it. The novel procedure is described in a publication that was released in Nature Structural & Molecular Biology's online edition on September 8.

Aneel Aggarwal, PhD, a senior author on the paper, notes that being able to see the methyltransferase domain of nsp14 in high resolution provides insights into how to build tiny compounds that fit into its active site and thereby hinder its crucial chemistry. At Mount Sinai's Icahn School of Medicine, he has the title of Professor of Pharmacological Sciences. We may now build small molecule inhibitors to add to the family of antivirals that work in tandem with vaccinations to treat SARS-CoV-2 with the help of medicinal chemists and virologists, thanks to this structural information.

Nirmatrelvir, molnupiravir, and remdesivir are prescription antivirals that target the major protease (MPro) enzyme and the RNA polymerase (nsp12) enzyme, respectively, of SARS-CoV-2. In labs all across the world, work to create novel antivirals that target various enzyme functions has been accelerating, and Mount Sinai's finding has considerably aided that work.

Dr. Aggarwal claims that "part of what drives our work" is the understanding obtained from treating HIV, which holds that "you normally need a cocktail of inhibitors for maximum efficacy against the virus."

Actually, the Mount Sinai research team created three distinct crystal structures of nsp14, each with a unique cofactor. They used these to decide which structure would make the best antiviral drug to prevent the RNA methyltransferase activity that the enzyme promotes and the virus requires to survive. According to their plan, the antiviral would substitute for the organic cofactor S-adenosylmethionine and obstruct the methyltransferase chemistry. The public now has access to the clarified crystal structures discovered by the researchers. They can now act as manuals for virologists and biochemists designing these chemicals all around the world.

The discovery was made feasible because researchers were able to overcome a challenge that had previously prohibited others from obtaining three-dimensional crystals of the nsp14 methytransferase domain. Lead author Jithesh Kottur, PhD, notes that "we used a method known as fusion-assisted crystallization." He is a scientist and postdoctoral fellow at Icahn Mount Sinai who specializes in crystallography. It includes combining the enzyme with a different, smaller protein that aids in crystallization.

The structural biologist Dr. Aggarwal is well known throughout the world. He emphasizes the significance of continuous research into a virus that has caused millions of fatalities worldwide by his field's researchers. The virus changes so quickly that it may become resistant to the antivirals that are now on the market, so we must keep creating new ones, he notes. Our research will help in the development of broad-spectrum antivirals for both current and upcoming coronavirus outbreaks because nsp14 exhibits great sequence conservation across coronaviruses and their variants (i.e., it does not mutate much).

Funding provided by the National Institutes of Health, the US Department of Energy, and the National Institute of General Medical Sciences

By MOUNT SINAI SCHOOL OF MEDICINE

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