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Scientists Identify Key Chemical Building Blocks for Antiviral Drug Against SARS-CoV-2

By HospiMedica International staff writers
Posted on 13 Jul 2020
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Image: The SARS-CoV-2 macro domain protein bound to small molecule fragments that could be the basis of novel antiviral drugs (Photo courtesy of UCSF)
Image: The SARS-CoV-2 macro domain protein bound to small molecule fragments that could be the basis of novel antiviral drugs (Photo courtesy of UCSF)
A team of scientists has identified key chemical building blocks for an eventual antiviral drug against SARS-CoV-2.

The new compounds identified by researchers from the UC San Francisco Quantitative Bioscience Institute Coronavirus Research Group (QCRG) in collaboration with Lawrence Berkeley National Laboratory (Berkeley Lab) and SLAC National Accelerator Laboratory (SLAC) bind to an enzyme produced by the virus, called the “macro domain,” which is known to be crucial for the virus’s ability to replicate in human cells. The study focused on poly (ADP-ribose) polymerases (PARPs), enzymes that play a major role in DNA repair and have been targeted by drugs to treat certain cancers.

The researchers set out to understand the molecular structure of the macro domain in order to identify small molecules with the right shape to jam the viral protein’s active site, the first step toward building an antiviral drug that could inhibit the virus’s spread by re-empowering PARPs’ protective tags. Using X-ray crystallography, they researchers grew crystals of isolated macro domain proteins, then bombarded these crystals with powerful X-rays, using the resulting diffraction patterns to infer a detailed picture of the macro domain’s atomic structure down to a resolution of nearly one angstrom, one millionth the diameter of a human hair. To identify small molecules capable of binding to the macro domain, the researchers used a technique called “fragment soaking” which involves creating hundreds of macro domain crystals, then using sound waves to manipulate candidate small molecules into the heart of each crystal and freezing them together in liquid nitrogen before returning to the X-ray light sources for further imaging. X-ray diffraction experiments revealed 13 small molecules, each about a third to a quarter the size of a normal drug molecule, that successfully bound to the macro domain, including four that bound to the enzyme’s active site.

Using the new information about what chemical structures can bind effectively to the macro domain’s active site, the researchers are now working with a virtual drug discovery platform to rapidly screen through half a billion potential drug-like molecules to find drug candidates that combine several of these potent chemical structures. According to the researchers, further work is needed to weld these potential active ingredients into a workable drug candidate, but the research represents a promising new frontier in the battle against the virus, particularly given uncertainties about the timing or ultimate efficacy of an eventual vaccine. The researchers have published their data directly online to accelerate global efforts to fight the coronavirus pandemic.

“The SARS-CoV-2 macro domain is not as well understood as the virus’s main protease or the spike proteins that other efforts are going after,” said James Fraser, PhD, an associate professor in the Department of Bioengineering and Therapeutic Sciences, based in the UCSF schools of Pharmacy and Medicine, who led the research effort as part of the UCSF QCRG Structural Biology Consortium. “We wanted to look where others aren’t looking as heavily and have succeeded in identifying some promising candidates to build drugs that could halt the virus’s ability to replicate and spread in the human body.”



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