3CLpro: The discovery of host cell substrates and its relevance as a drug target for SARS-CoV-2 variants of concern


  • Kristi Lichimo UBC


The virally-encoded proteases 3CLpro and PLpro are essential for SARS-CoV-2 replication. Since the onset of COVID-19, 3CLpro has been considered as a desirable drug target due to its conserved structure and function amongst coronaviruses and SARS-CoV-2 variants. 3CLpro and PLpro are known to cleave viral polyproteins post-translation, yielding non-structural proteins with different roles in the SARS-CoV-2 life cycle. However, recent studies have demonstrated that 3CLpro proteolytic activity is not only limited to viral proteins. 3CLpro has been shown to cleave an extensive range of host cell substrates, thereby subverting host antiviral responses to infection. Terminal Amine Isotopic Labelling of Substrates (TAILS) has identified at least 101 host cell proteins that are cleaved by 3CLpro during infection. Many of these substrates are involved in relevant biological pathways, including type I interferon signaling, cell differentiation and morphology, and autophagy. The implications for the host’s antiviral response and therapeutic drug development remain poorly understood. In addition, 3CLpro in SARS-CoV-2 variants of concern harbors point mutations, potentially undermining its suitability as a therapeutic drug target. This article will provide a comprehensive review of 1) the recent discovery of the 3CLpro host cell degradome and how it subverts antiviral responses, and 2) whether mutations in 3CLpro compromise the efficacy of 3CLpro inhibitors, including PAXLOVIDTM, to treat SARS-CoV-2 variants of concern. Given this new insight on the mechanism of 3CLpro, we must understand why this protease requires so many host targets to hijack the immune system. The mutations and multifaceted function of 3CLpro are worth further investigation to justify the approval of therapeutic drugs targeting 3CLpro, and to reduce the clinical burden of the most concerning SARS-CoV-2 variants worldwide.