In December 2020 the Foundation made a grant to the University of Texas, Southwestern (UTSW) Medical Center in Dallas, to understand the biochemical functions of mysterious proteins called “pseudoenzymes.” While our chromosomes contain genes to encode almost 3,000 enzymes with identified catalytic functions, there are many more which can be seen in the DNA sequence but with unknown functions. Likewise, there are mystery genes in all non-human organisms, including those that infect us and cause disease. In this Keck project, an early career investigator at UTSW, Vincent (Vinnie) Tagliabracci, and three coinvestigators (Krzysztof Pawlowski, Diana Tomchick and John Schoggins), set out to solve some of these mysteries and find functions for some pseudoenzymes. The project soon turned to a very topical target: a pseudoenzyme in the COVID virus genome. Vinnie and his team were able to show that a COVID gene called “nsp12” encodes a protein that completes the RNA genome of the virus by adding a chemical “cap” to its front end. This cap is necessary for the virus to infect us, and so is a new possible target for anti-viral drugs. Their work was published in Nature in 2022 and could lead to a new class of anti-viral drugs, useful against COVID and related coronaviruses. More recently, they went on to test more than a third of a million compounds and found one that acts to inhibit the nsp12 viral RNA capping enzyme. Since he received this Keck grant, Tagliabracci has been promoted to associate professor at UTSW, and he was appointed as a Howard Hughes Medical Institute Investigator (in 2021) and he received the Edith and Peter O’Donnell Award in Biological Sciences from The Academy of Medicine, Engineering and Science of Texas in 2024.
