SARS-CoV-2 replicase polyprotein 1ab (ORF1ab)

The SARS-CoV-2 ORF1ab polyprotein is the largest protein product of the SARS-CoV-2 genome, comprising approximately two-thirds of the viral RNA. It is translated as a massive precursor, pp1ab, which is autoproteolytically cleaved by the viral main protease (Mpro/nsp5) and papain-like protease (PLpro/nsp3) into 16 individual non-structural proteins (nsps). These nsps assemble into the replication-transcription complex (RTC), which is responsible for viral RNA synthesis, proofreading, and capping. Conserved peptide epitopes within ORF1ab are of particular interest for vaccine development because they are highly stable across different variants of concern, unlike the rapidly mutating spike protein. Targeting these epitopes, as seen with the mRNA vaccine candidate BNT162b4, aims to induce broad-spectrum T-cell immunity that can recognize and eliminate infected cells regardless of surface mutations. Additionally, the enzymatic components of the polyprotein, such as the RNA-dependent RNA polymerase (nsp12), serve as the primary targets for established antiviral drugs like remdesivir and molnupiravir.

Other names

Replicase polyprotein 1abpp1abORF1a/bSARS-CoV-2 ORF1ab polyproteinPolyprotein 1ab

Protease inhibition, RNA-dependent RNA polymerase inhibition, T-cell activation