Thomas E. Smithgall, PhD
- William S. McEllroy Professor, Department of Microbiology and Molecular Genetics
Education & Training
- Postdoctoral Fellow, National Cancer Institute, NIH
- PhD in Pharmacology, University of Pennsylvania School of Medicine
- BA in Biochemistry, University of Pennsylvania
While current antiretroviral drugs have transformed HIV infection from a life-threatening illness to a chronic condition, they do not clear the virus from the patient and require life-long administration. Chronic antiretroviral drug exposure can be toxic and promote drug resistance, underscoring the urgent need for new approaches to combat HIV. We have discovered compounds that interfere with the functions of HIV-1 Nef as a new approach to antiretroviral therapy. Unique to primate lentiviruses, Nef is critical for HIV-1 replication in vivo, immune escape of HIV-infected cells, and AIDS progression. Our small molecule HIV-1 Nef inhibitors potently suppress HIV replication and restore immune recognition of HIV-positive cells, raising the exciting possibility of their translational potential in new strategies to eliminate latent viral reservoirs. In addition to HIV, our lab is also exploring new approaches to precision therapy for myeloid leukemia. Protein-tyrosine kinases represent exciting drug targets for leukemia and many other cancers. Most current kinase inhibitors compete for ATP binding at the kinase domain active site. However, structural conservation of kinase active sites limits the clinical applications of ATP-competitive kinase inhibitors as well as their utility as chemical probes of individual kinase functions. To address these issues, we are pursuing drug discovery strategies for small molecules that enhance the natural allosteric mechanisms associated with kinase domain regulation. Chemical library screening assays based on this concept are targeting members of the Src and Tec/Btk kinase families. Allosteric inhibitors of these kinases are anticipated to have utility in the treatment of cancer and infectious diseases.
Li, W.F., Aryal, M., Shu, S.T. and Smithgall, T.E. HIV-1 Nef dimers short-circuit immune receptor signaling by activating Tec-family kinases at the host cell membrane. J. Biol. Chem. 295: 5163–5174, 2020
Patel, R.K., Patel, Y.K., and Smithgall, T.E. In Vitro Evolution Reveals a Single Mutation as Sole Source of Src-Family Kinase C-Helix-out Inhibitor Resistance. ACS Chem. Biol. 15: 2175–2184, 2020.
Shi, H., Tice, C.M., Emert-Sedlak, L., Chen, L., Li, W.F., Carlsen, M., Wrobel, J.E., Reitz, A.B. and Smithgall, T.E. Tight-binding Hydroxypyrazole HIV-1 Nef Inhibitors Suppress Viral Replication in Donor Mononuclear Cells and Reverse Nef-mediated MHC-I downregulation. ACS Infectious Dis. 6: 302-312, 2020.
Staudt, R.P., Alvarado, J.J., Emert-Sedlak, L.A., Shi, H., Shu, S.T., Wales, T.E., Engen, J.R., and Smithgall, T.E. Structure, function, and inhibitor targeting of HIV-1 Nef-effector kinase complexes. J. Biol. Chem. 295: 15158-15171, 2020 (Review).
Shen, K., Moroco, J.A., Patel, R.K., Shi, H., Engen, J.R., Dorman, H.R. and Smithgall, T.E. The Src-family kinase Fgr is a transforming oncoprotein independent of SH3-SH2 domain regulation. Science Signaling 11: eaat5916, 2018.