Klatskin-Sutker Discovery Fund award supports development of novel antivirals at the LSI

In early 2020, many scientists at the University of Michigan Life Sciences Institute quickly launched new projects to improve understanding of the fundamental mechanisms underlying SARS-CoV-2 infection.

One of those new research projects is now advancing a novel approach to developing antivirals against SARS-CoV-2, with support from the LSI’s Klatskin-Sutker Discovery Fund.

Although vaccines to prevent severe COVID-19 infection are beginning to roll out, it will remain important to develop treatments for those infections that do occur. Many therapeutic approaches have focused on interactions between spike proteins on the surface of the viral particle and a receptor protein on the surface of human cells. This receptor protein, called ACE2 (short for “angiotensin-converting enzyme 2”), provides an entry point where the virus can latch onto and begin infecting human cells.

But LSI faculty member Anna Mapp, Ph.D., is interested in another protein-protein interaction that may have more far-reaching therapeutic effects: the virus's interaction with transmembrane protease, serine 2 (or TMPRSS2). The virus relies on this human protein to prime its spike protein before it can bind to ACE2. Previous research has found that TMPRSS2 can strongly promote viral infection, and mice that lack this protein were resistant to a variety of coronaviruses, not just the virus that causes COVID-19.

“An inhibitor that blocks TMPRSS2 effectively could be broadly useful against viral infection,” Mapp explains. “But the only existing inhibitors are not attractive therapeutic options because they are not selective enough to efficiently block TMPRSS2 without affecting other serine proteases.” 

With Klatskin-Sutker funds, Mapp will apply her expertise in targeting challenging protein-protein interactions to investigate new options for interrupting the activity of TMPRSS2 — with the hope of ultimately blocking infection not only by SARS-CoV-2 but other coronaviruses as well. This is a collaborative effort with U-M professors Charles L. Brooks III, Ph.D., Matthew Soellner, Ph.D. and Corey Stephenson, Ph.D.

As one approach, the team is searching for new locations to target on the TMPRSS2 molecule, other than the protein’s main active site. Such so-called allosteric sites often offer pathways to disrupt protein activity specifically on a single target and to avoid activity on related proteins.