Small-molecule induced protein degradation of antiviral targets
Priscilla Yang, PhD
Department of Microbiology and Blavatnik Institute Harvard Medical School, Boston, Massachusetts, United States of America
Recently developed methods for small molecule-induced degradation of specific proteins rely on chimeric molecules with moieties that bind the target of interest and a specific E3 ubiquitin ligase. Small molecule-binding to both partners leads to ubiquitination and proteasomal degradation of the target. This event-driven (rather than occupancy-driven) pharmacology ablates all of the target’s functions by removing it from the cell. Although this approach has the potential to be useful as an antiviral strategy, strong viral expression and localization of viral proteins on or near specialized membranes might limit the susceptibility of viruses to this approach. We recently leveraged existing inhibitors to develop cereblon- and von Hippel-Lindau-based degraders of the hepatitis C virus NS3 protein and showed that target degradation plays a significant role in the antiviral activity of these compounds. We further tested the idea that the event-driven pharmacology of these agents would render them more resilient to mutations that reduce target-binding and showed that NS3-targeting degraders can overcome viral variants that confer resistance to conventional NS3-4A inhibitors. We have recently extended our efforts to examine susceptibility of other antiviral targets, including those that do not reside in the cytoplasm and others that are considered “undruggable,” to small molecule-induced degradation. Our goal is to provide proof-of-concept for targeted protein degradation as a new strategy for antivirals development and to develop tools for systematic development of antiviral degraders.
The International Society for Antiviral Research (ISAR) is an internationally recognized organization for scientists involved in basic, applied, and clinical aspects of antiviral research. The Society main event is the annual International Conference on Antiviral Research (ICAR), a truly interdisciplinary meeting which attracts the interest of chemists, biologists, and clinicians.