UVA Chemical Engineering Lab Helps Defeat COVID-19 with Science Funded by CARES Act
On April 3, 2020, as COVID-19 was already ravaging some U.S. communities, the National Science Foundation issued a call for non-medical, immediately implementable research to fight the disease as part of CARES, Congress’ Coronavirus Aid, Relief and Economic Security Act. Within a week, University of Virginia associate professor of chemical engineering Bryan Berger and his longtime collaborator, Jeffery Klauda, responded.
Berger and Klauda, an associate professor in the Department of Chemical and Biomolecular Engineering at the University of Maryland, proposed combining the power of mathematical modeling with high-throughput testing to fast-track answers crucial to understanding how SARS-CoV-2, the coronavirus that causes COVID-19, propagates within its human host. High-throughput research automates experiments to increase the number that can be performed and speed the time to discovery.
Berger and Klauda each received a $150,000 EAGER award under the same title, “Design of Inhibitors for ORF7a and ORF7b Oligomerization in COVID-19.” EAGER, the National Science Foundation’s Early Concepts Grant for Exploratory Research funding program, is designed for untested but potentially transformative research approaches. The grants will support Berger and Klauda’s study of proteins linked to the virulence of SARS-CoV-2 in humans using integrated experimental and computational methods.
The viral proteins, named ORF7a and ORF7b, form larger protein complexes unique to coronaviruses.
“There is evidence these complexes are important in preventing proper host immune recognition and response,” Berger said. “ORF7a and ORF7b are not well understood, but previous studies suggest they are key for rapid spread during infection — i.e., they dampen the individual’s immune response, so the virus can propagate more quickly once an infection happens.”
The UVA team — which includes recent chemical engineering Ph.D. graduate James Tang, who is now a postdoctoral research associate at UVA, chemical engineering Ph.D. student Madison Mann and biomedical engineering Ph.D. student Nathanael Sallada — have developed new experimental methods to study how the viral proteins interact with other human proteins. Klauda will use this information to inform models to predict how ORF7a and ORF7b proteins interact with other proteins important in immune response.
“Our focus is on studying the viral interactions with the host at a molecular level,” Berger said. “Jeff’s simulations are essential to help inform and design better experiments, as well as understand the results of those experiments. We will develop models of these interactions and methods to study them in the lab so that others can use the results for further research.”
Among their innovations, the UVA team developed new high-throughput screening tests to rapidly identify peptides, short chains of amino acids making up proteins, that inhibit oligomerization — the chemical process through which proteins such as ORF7a and ORF7b form into larger protein structures. The aim is to design peptide probes of oligomerization, which can be applied in patients and studied for the roles they may play in viral infection.
“Importantly, the integration of computational methods will enable us to reduce time and effort to rapidly generate models of oligomerization that will be important in informing future therapeutic design or mechanistic studies of viral propagation,” Berger said.
Berger and Klauda plan to share the findings of their research with the scientific community. In particular, Berger’s lab will provide the tools it develops free through Addgene, a global nonprofit repository for genetic materials used in biomolecular research. Another outcome of the work will be training for graduate students and post-doctoral fellows in the experimental and computational methods that result from their research.