Researchers used a variety of advanced drug screening techniques to test out more than 10,000 compounds in search of a cure. To their surprise, they found that the widely used antibiotic methacycline was effective at preventing brain infections and reducing neurological problems associated with the virus in mice.
«Around the world, the Zika outbreak produced devastating, long-term neurological problems for many children and their families. Although the infections are down, the threat remains,» said Avindra Nath, M.D., senior investigator at the NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and a senior author of the study published in PNAS. «We hope these promising results are a good first step to preparing the world for combating the next potential outbreak.»
The study was a collaboration between scientists on Dr. Nath’s team and researchers in laboratories led by Anton Simeonov, Ph.D., scientific director at the NIH’s National Center for Advancing Translational Sciences (NCATS) and Radhakrishnan Padmanabhan, Ph.D., Professor of Microbiology & Immunology, Georgetown University Medical Center, Washington, D.C.
The Zika virus is primarily spread by the Aedes aegypti mosquito. In 2015 and 2016, at least 60 countries reported infections. Some of these countries also reported a high incidence of infected mothers giving birth to babies born with abnormally small heads resulting from a developmental brain disorder called fetal microcephaly. In some adults, infections were the cause of several neurological disorders including Guillain-Barre syndrome, encephalitis, and myelitis. Although many scientists have tried, they have yet to discover an effective treatment or vaccination against the virus.
In this study, the researchers looked for drugs that prevent the virus from reproducing by blocking the activity of a protein called NS2B-NS3 Zika virus protease. The Zika virus is a protein capsule that carries long strings of RNA-encoded instructions for manufacturing more viral proteins. During an infection, the virus injects the RNA into a cell, resulting in the production of these proteins, which are strung together, side-by-side, like the parts in a plastic model airplane kit. The NS2B-NS3 protease then snaps off each protein, all of which are critical for assembling new viral particles.
«Proteases act like scissors. Blocking protease activity is an effective strategy for counteracting many viruses,» said Rachel Abrams, Ph.D., an organic chemist in Dr. Nath’s lab and the study leader. «We wanted to look as far and wide as possible for drugs that could prevent the protease from snipping the Zika virus polyprotein into its active pieces.»
To find candidates, Dr. Abrams worked with scientists on Dr. Simeonov’s and Dr. Padmanabhan’s teams to create assays, or tests, for assessing the ability of drugs to block NS2B-NS3 Zika virus protease activity in plates containing hundreds of tiny test tubes. Each assay was tailored to a different screening, or sifting, technique. They then used these assays to simultaneously try out thousands of candidates stored in three separate libraries.
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Materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Content may be edited for style and length.