By mid-March, researchers from around the country had usedAPSbeamlines to characterize roughly a dozen proteins from SARS-CoV-2, several of them with inhibitors.

The fortunate thing is that we have a bit of a head start, said Bob Fischetti, life sciences advisor to theAPSdirector. This virus is similar but not identical to theSARSoutbreak in2002, and70structures of proteins from several different coronaviruses had been acquired using data fromAPSbeamlines prior to the recent outbreak. Researchers have background information on how to express, purify and crystallize these proteins, which makes the structures come more quickly right now about a few a week.

One of the research teams performing work on SARS-CoV-2includes members of the Center for Structural Genomics of Infectious Diseases (CSGID), which is funded byNIHs National Institute of Allergy and Infectious Diseases (NIAID). The team is led by Karla Satchell from Northwestern University and Andrzej Joachimiak of Argonne and the University of Chicago. Other members involved in the work include Andrew Mesecar from Purdue University and Adam Godzik from the University of California, Riverside. They have usedAPSbeamlines19-ID-D, operated by the Argonne Structural Biology Center, supported by theDOEOffice of Science, and21-ID, operated by the Life Sciences Collaborative Access Team, a multi-institution consortium supported by supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor.

Another group, led by M. Gordon Joyce at the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc. (HJF) at the Walter Reed Army Institute of Research (WRAIR) is studying antibody and antiviral compounds. They are using beamline24-ID, which is operated by the Northeastern Collaborative Access Team, which is managed by Cornell University and seven member institutions.

According to Fischetti, the breakneck pace of collaborative science with one common essential goal is unlike anything else he has seen in his career. Everything is just moving so incredibly fast, and there are so many moving pieces that its hard to keep up with, he said.

Fischetti compared finding the right inhibitor for a protein to discovering a perfectly sized and shaped Lego brick that would snap perfectly into place. These viral proteins are like big sticky balls we call them globular proteins, he said. But they have pockets or crevices inside of them where inhibitors might bind.

By using the X-rays provided by theAPS, scientists can gain an atomic-level view of the recesses of a viral protein and see which possible inhibitors either pre-existing or yet to be developed might reside best in the pockets of different proteins.

The difficulty with pre-existing inhibitors is that they tend to bind with only a micromolar affinity, which would require extremely high doses that could cause complications. According to Fischetti, the research teams are looking for an inhibitor that would have a nanomolar affinity, enabling it to be administered as a drug that would have many fewer or no side effects.

This situation makes clear the importance of science in solving critical problems facing our world, saidAPSDirector Stephen Streiffer. X-ray light sources, including theAPS, our sisterDOEfacilities, and the light sources around the world, plus the researchers who use them are fully engaged in tackling this dire threat.

Computing theCOVID-19crisis

Researchers can accelerate a significant part of inhibitor development through the use of supercomputing. Just as light sources from around the world, including the Diamond Light Source in the United Kingdom, have banded together to solve SARS-CoV-2protein structures, so too have the top supercomputers turned their focus to the challenge at hand.

As part of theCOVID-19High Performance Computing Consortium, recently announced by President Trump, researchers at Argonne are joining forces with researchers from government, academia, and industry in an effort that combines the power of16different supercomputing systems.

At Argonne, researchers using the Theta supercomputer at the Argonne Leadership Computing Facility also a DOE Office of Science User Facility have linked up with other supercomputers from around the country, including Oak Ridge National Laboratorys Summit supercomputer, the Comet supercomputer at the University of California-San Diego, and the Stampede2 supercomputer at the Texas Advanced Computing Center. With their combined might, these supercomputers are powering simulations of how billions of different small molecules from drug libraries could interface and bind with different viral protein regions.

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Argonne's Researchers and Facilities Playing a Key Role in the Fight Against COVID-19 - HPCwire