Development of novel chemical probes and SARS-CoV-2 antiviral therapeutics through engineered HAI-2 protein inhibitors of TMPRSS proteases

Respiratory viruses exploit the biological activity of human proteins present at the surface of airway cells to allow viruses to penetrate that physical barrier and subsequently replicate in infected cells. It has been established that a family of human proteins, the type 2 transmembrane serine proteases, are directly responsible for this viral entry, but they have been challenging to develop drugs against because they have been unable to be studied in isolation. Our group developed the leading strategy to isolate and study one of these proteins, transmembrane protease, serine-2 (TMPRSS2), which is exploited by coronaviruses (including SARS-CoV-2) and Influenza A/B viruses, for entry of the airways. Our access to TMPRSS2 enabled us to determine its 3D molecular structure for the first time, an important advancement that paves the way for the development of highly specific TMPRSS2 drugs that could block viral entry. Importantly, drugs blocking TMPRSS2 may be insensitive to emerging virus mutations because TMPRSS2 is such an important human protein for infection. By modifying the protein known to regulate TMPRSS2 activity, HAI-2, we engineered highly effective TMPRSS2 inhibitors.

Faculty Supervisor:

Cheryl Arrowsmith

Student:

Partner:

Structural Genomics Consortium

Discipline:

Life Sciences

Sector:

Professional, scientific and technical services

University:

University of Toronto

Program: