Targeted protein degraders of SARS-CoV-2 Mpro demonstrate superior antiviral activity over enzymatic inhibition alone and potency against nirmatrelvir resistant virus
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Targeted viral protein degraders, which enable physical elimination of viral protein target to inhibit all its primary and ancillary functions, could provide a new avenue to more effective antiviral drugs, overcoming the limitations associated with conventional inhibition-based direct-acting antiviral approaches, such as the selection of antiviral resistance. We have adapted SARS-CoV-2 Mpro inhibitors into a panel of targeted protein degraders and found three compounds, derived from clinically approved nirmatrelvir and utilising VHL or IAP ubiquitin ligase recruiters, capable of degrading Mpro protein in a concentration, time and host proteasomal dependent fashion, whereas size matched non-degrading controls and nirmatrelvir could not. The compounds also degraded nirmatrelvir-resistant mutant Mpro protein and demonstrated enhanced anti-SARS-CoV-2 antiviral activity against multiple wildtype and nirmatrelvir-resistant strains compared to precisely matched non-degrading control molecules. This work demonstrates the feasibility of generating targeted protein degraders from established viral protein inhibitors and confirms that degraders possess superior antiviral potency compared to size matched enzymatic inhibitors.
