ORF1ab

ORF1ab is a large open reading frame at the 5' end of the coronavirus genome that encodes the virus’s main non-structural proteins. It lies in a genomic region separate from the genes that encode structural proteins such as spike (S), envelope (E), membrane (M), and nucleocapsid (N). ORF1ab together with ORF1a forms the majority of the viral coding sequence and is essential for replication and transcription.

Translation of ORF1ab involves a -1 ribosomal frameshift at the ORF1a/ORF1b overlap. This allows the ribosome to switch reading frames and produce a longer polyprotein, pp1ab, from ORF1a and ORF1b in a controlled proportion. The initial product from ORF1a is pp1a, while the frameshift allows production of pp1ab. The resulting polyproteins are then cleaved by viral proteases, principally the papain-like protease (PLpro) and the 3C-like protease (3CLpro, also called nsp5), into 16 non-structural proteins (nsps 1–16).

The non-structural proteins form the viral replication-transcription complex. Key components include the RNA-dependent RNA polymerase (nsp12) with cofactors nsp7 and nsp8, a helicase (nsp13), an exoribonuclease (nsp14) with cofactors, and a 2'-O-methyltransferase (nsp16) involved in RNA capping. Collectively, these nsps carry out genome replication and the transcription of subgenomic RNAs that code for structural and accessory proteins.

ORF1ab is highly conserved among coronaviruses and is a frequent focus of antiviral research, as disruption of its encoded replication machinery can halt viral propagation.