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UrduThe enzyme, known as nsp14, has a crucially important region known as the RNA methyltransferase domain, which has eluded previous attempts by the scientific community to characterize its three-dimensional crystal structure. A paper describing the innovative process was published in the September 8 online edition of Nature Structural & Molecular Biology [DOI: 10.1038/s41594-022-00828-1].
“Being able to visualize the shape of the methyltransferase domain of nsp14 at high resolution gives us insights into how to design small molecules that fit into its active site, and thus inhibit its essential chemistry,” says senior author Aneel Aggarwal, PhD, Professor of Pharmacological Sciences at the Icahn School of Medicine at Mount Sinai. “With this structural information, and in collaboration with medicinal chemists and virologists, we can now design small molecule inhibitors to add to the family of antivirals that go hand-in-hand with vaccines to combat SARS-CoV-2.”
Prescription antivirals that target key enzymes of SARS-CoV-2 include nirmatrelvir for the main protease (MPro) enzyme, and molnupiravir and remdesivir for the RNA polymerase (nsp12) enzyme. Research to develop new antivirals targeting different enzymatic activities has been accelerating in laboratories around the world, and Mount Sinai’s discovery has added significantly to that effort.
“Part of what drives our work,” says Dr. Aggarwal, “is the knowledge gained from treating HIV—that you typically need a cocktail of inhibitors for maximum impact against the virus.”
The Mount Sinai team actually developed three crystal structures of nsp14, each with different cofactors, from which they identified the best scaffold for the design of antivirals for inhibiting the RNA methyltransferase activity that the enzyme enables and the virus needs to survive. According to their scheme, the antiviral would take the place of the natural cofactor S-adenosylmethionine, thus preventing the methyltransferase chemistry from occurring. The crystal structures that the team has elucidated have been made available to the public and will now serve as guides for biochemists and virologists globally to engineer these compounds.
Making the discovery possible was the ability of researchers to clear a hurdle that had prevented others in the past from creating three-dimensional crystals of the nsp14 methytransferase domain. “We employed an approach known as fusion-assisted crystallization,” explains lead author Jithesh Kottur, PhD, a postdoctoral fellow at Icahn Mount Sinai, and a crystallographer and biochemist. “It involves fusing the enzyme with another small protein that helps it to crystalize.”
Dr. Aggarwal, an internationally recognized structural biologist, underscores the importance of ongoing investigative work by researchers in his field against a virus that has led to millions of deaths globally. “The virus evolves so quickly that it can develop resistance to the antivirals now available, which is why we need to continue developing new ones,” he observes. “Because of the high sequence conservation of nsp14 across coronaviruses and their variants (meaning it does not mutate much), our study will aid in the design of broad-spectrum antivirals for both present and future coronavirus outbreaks.”
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About the Icahn School of Medicine at Mount Sinai
The Icahn School of Medicine at Mount Sinai is internationally renowned for its outstanding research, educational, and clinical care programs. It is the sole academic partner for the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.
Ranked 14th nationwide in National Institutes of Health (NIH) funding and among the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges, Icahn Mount Sinai has a talented, productive, and successful faculty. More than 3,000 full-time scientists, educators and clinicians work within and across 34 academic departments and 35 multidisciplinary institutes, a structure that facilitates tremendous collaboration and synergy. Our emphasis on translational research and therapeutics is evident in such diverse areas as genomics/big data, virology, neuroscience, cardiology, geriatrics, as well as gastrointestinal and liver diseases.
Icahn Mount Sinai offers highly competitive MD, PhD, and Master’s degree programs, with current enrollment of approximately 1,300 students. It has the largest graduate medical education program in the country, with more than 2,000 clinical residents and fellows training throughout the Health System. In addition, more than 550 postdoctoral research fellows are in training within the Health System.
A culture of innovation and discovery permeates every Icahn Mount Sinai program. Mount Sinai’s technology transfer office, one of the largest in the country, partners with faculty and trainees to pursue optimal commercialization of intellectual property to ensure that Mount Sinai discoveries and innovations translate into healthcare products and services that benefit the public.
Icahn Mount Sinai’s commitment to breakthrough science and clinical care is enhanced by academic affiliations that supplement and complement the School’s programs.
Through the Mount Sinai Innovation Partners (MSIP), the Health System facilitates the real-world application and commercialization of medical breakthroughs made at Mount Sinai. Additionally, MSIP develops research partnerships with industry leaders such as Merck & Co., AstraZeneca, Novo Nordisk, and others.
The Icahn School of Medicine at Mount Sinai is located in New York City on the border between the Upper East Side and East Harlem and classroom teaching takes place on a campus facing Central Park. Icahn Mount Sinai’s location offers many opportunities to interact with and care for diverse communities. Learning extends well beyond the borders of our physical campus, to the eight hospitals of the Mount Sinai Health System, our academic affiliates, and globally.
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* Mount Sinai Health System Member Hospitals: The Mount Sinai Hospital; Mount Sinai Queens; Mount Sinai Beth Israel; Mount Sinai West (previously known as Mount Sinai Roosevelt); Mount Sinai Morningside (previously known as Mount Sinai St. Luke’s); Mount Sinai Brooklyn; New York Eye and Ear Infirmary of Mount Sinai; and Mount Sinai South Nassau (previously known as South Nassau Communities Hospital).
