Forty years with coronaviruses

Weiss, Susan R.

Virions contain the genetic material and the structural proteins necessary for invasion. Early studies on the viral structural proteins by Kathryn Holmes and Larry Sturman (Frana et al., 1985) showed that the MHV spike protein (S, initially called E2) was synthesized as a precursor, and during intracellular processing, is proteolytically cleaved by the cellular enzyme furin into S1 and S2 subunits. Spike protein cleavage was required for cell-to-cell fusion during infection and was both cell type dependent and virus strain dependent. Much later, it was found that a second cleavage S29 exposes the fusion peptide and is thus necessary for viral entry. These early findings informed many subsequent studies on SARS-CoV and MERS-CoV, defining where cleavages occur and which proteases carry them out. These seemingly nuanced studies demonstrated that these details impact entry routes, cellular and organ tropism, and possibly antiviral targets (Millet and Whittaker, 2015) . The sequence of SARS-CoV-2 was released within weeks of the outbreak, and it was clear that the SARS-COV-2 spike protein has a furin cleavage site in the S1/S2 junction, different from SARS-CoV and other closely related bat viruses (Coutard et al., 2020) . This has implications for viral entry routes and possible protease inhibitors as antivirals, and has led to speculation about virulence and pathogenesis. Interestingly, this new furin site may serve as a marker to identify a possible precursor virus.