SARS-CoV-2 Open Reading Frame 1ab (ORF1ab) (ORF1ab)

SARS-CoV-2 Open Reading Frame 1 (ORF1) is the primary genetic region of the SARS-CoV-2 virus, comprising approximately 21 kilobases and encoding the essential machinery for viral replication. It consists of two overlapping frames, ORF1a and ORF1b, which are translated into the polyproteins pp1a and pp1ab through a -1 ribosomal frameshift mechanism (UniProt P0DTD1). These polyproteins are autoproteolytically processed by the viral proteases Mpro (nsp5) and PLpro (nsp3) into 16 non-structural proteins (nsps) that assemble into the replicase-transcriptase complex (PubMed: 32275855). This complex includes the RNA-dependent RNA polymerase (nsp12), which is the direct target of antivirals like Remdesivir and Molnupiravir, and the main protease, which is targeted by Nirmatrelvir (NIH: COVID-19 Treatment Guidelines). Because the proteins encoded by ORF1 are indispensable for the viral life cycle and often lack direct human orthologs, they represent the most significant therapeutic targets for small-molecule antiviral development against COVID-19. Additionally, the ORF1ab sequence is a standard target for diagnostic RT-PCR assays used to detect active SARS-CoV-2 infection.

Other names

ORF1aORF1bReplicase polyprotein 1abpp1abpp1aSARS-CoV-2 replicase gene

Inhibition of viral RNA-dependent RNA polymerase (RdRp) to terminate RNA chain elongation or induce lethal mutagenesis, and inhibition of viral proteases (Mpro/3CLpro and PLpro) to prevent polyprotein processing.