Researchers at the Icahn School of Medicine at Mount Sinai are working on the basic science that lays the groundwork to finding a way to treat and prevent the Zika virus, a global health risk. In two papers published this fall, one in the journal Nature Structural & Molecular Biology, and the other in the journal Cell Reports, researchers identified the three-dimensional shapes of two enzymes critical to replication and survival of the virus.
The first study looked at the enzyme NS3, which unwinds RNA and is essential for the virus's replication. The second study examined the enzyme NS5, which is responsible for capping the viral genome, which is vital in the creation of stable RNA for viral replication. Both studies were performed by a team led by Aneel Aggarwal, PhD, Professor of Pharmacological Sciences and Oncological Sciences at the Icahn School of Medicine at Mount Sinai, and which also included Rinku Jain, PhD, Assistant Professor of Pharmacological Sciences, and Adolfo García-Sastre, PhD, Professor of Microbiology and Director of the Global Health & Emerging Pathogens Institute at the Icahn School of Medicine at Mount Sinai, as well as their former colleague Javier Colomo, PhD.
"Determining the three-dimensional structures of a virus and its enzymes is a crucial prerequisite for structure-based drug discovery," said Dr. Aggarwal. "Once we know the precise shape of these entities, we can work on inhibiting them."
Drug development within the field of structural biology relies on high-resolution three-dimensional structures coupled with computational and medicinal chemistry. While the same enzymes exist in other flaviviruses (such as Dengue and West Nile), the exact shape of the enzymes is different in each virus. In these studies, Dr. Aggarwal and his team identified the shape of the enzymes in a short amount of time and immediately made their results available to researchers throughout the world working to find an effective treatment for Zika virus.
"The next step would be to develop compounds to inhibit these enzymes' actions by physically blocking them, interfering with the reproduction of the virus," said Dr. Aggarwal. "We are fortunate to be able to collaborate with some of the best computational and medicinal chemists and virologists right here at Mount Sinai."
The Zika virus has emerged as a major health concern over the past year, spreading rapidly across parts of South and Central America, as well as some parts of North America. It has been linked to birth defects in newborn infants and Guillain-Barré syndrome in adults. At this point, there is no effective way of preventing infection once people are exposed to Zika-carrying mosquitoes.
"We hope this work will lead to the development of effective treatments that help alleviate the terrible effects of Zika, and we see ourselves as part of a world-wide effort," said Dr. Aggarwal.
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