Developing Inhibitors of Viral and Metazoan mRNA Cap N7-G Methyl Transferases

Event Details

Type

Monday Lecture Series

Speaker(s)

Thomas Tuschl, Ph.D., F. M. Al Akl, M.D. and Margaret Al Akl Professor and head, Laboratory of RNA Molecular Biology, The Rockefeller University

Speaker bio(s)

Cytosolic replicating RNA and DNA viruses encode proteins critical for viral genome replication, mRNA translation, and evasion from innate immunity. These proteins often include guanine-N7- and 2’-O-methyltransferases for capping of viral RNAs and are essential for viral replication. The Tuschl Lab is developing drug screens for inhibition of these MTases and obtained a first-in-class non-covalent small-molecule inhibitor of the viral guanine-N7 methyltransferase (MTase) NSP14 of SARS-CoV-2. The drug inhibited NSP14 by forming a unique ternary S-adenosylhomocysteine (SAH)-bound complex. Medicinal chemistry hit-to-lead optimization resulted in TDI-015051 with a KD of 39 pM and an EC50 of 11 nM inhibiting virus infection in a cell-based system. TDI-015051 also inhibited viral replication in vivo in a transgenic mouse model of SARS-CoV-2 infection with an efficacy comparable to the FDA-approved reversible covalent protease inhibitor nirmatrelvir. The inhibition of viral cap methylases as antiviral strategy is also adaptable to other viruses of pandemic concern.

Thomas Tuschl is the F. M. Al Akl, M.D. and Margaret Al Akl Professor and head of the Laboratory of RNA Molecular Biology at The Rockefeller University. He received his Ph.D. in chemistry from the University of Regensburg and the Max Planck Institute for Experimental Medicine in Göttingen, Germany. He was a postdoctoral fellow at the Massachusetts Institute of Technology/Whitehead Institute, and then a group leader at the Max Planck Institute for Biophysical Chemistry, Göttingen. He received numerous awards recognizing his contributions to uncovering small-RNA-guided gene regulation and its adaptation to human gene silencing. He is a member of the German Academy of Sciences Leopoldina. Tuschl is cofounder of Alnylam Pharmaceuticals, a Boston-based biotech company producing siRNA drugs, and a cofounder of Ventus Therapeutics, a Boston- and Montreal-based pharmaceutical company developing antagonists of innate immunity responses. His research is primarily focused on posttranscriptional gene regulatory mechanisms and the role of non-coding RNA and RNA-binding proteins in general.

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Open to

Campus Only