Non-canonical RNA dependent RNA polymerase (RdRp) activity of ORF8 protein in SARS-CoV-2: Equivocal biological significance
Abstract
No current treatment options were successful in containing the ongoing
pandemic COVID-19 caused by SARS-CoV-2. It is essential to understand
the molecular players of SARS-CoV-2 to find a suitable treatment method
and to develop an effective antiviral drug as early as possible. Global
researchers have undertaken accelerated structural studies of key
proteins involved in host-virus interaction, replication, and
transcription. In silico studies support structural biologist with
preliminary information to efficiently drive further studies and
characterization. From the genome sequence, most SARS-CoV-2 annotated
ORF has a conserved sequence similar to SARS-CoV-1, except for ORF8 and
ORF10. The function of ORF8 protein in SARS-CoV-2 is uncertain. Herein,
we had modelled the ORF8 protein and studied its putative function using
various substrates as a probe to determine its biological significance.
The modelled SARS-CoV-2 (mORF87A) protein shows IgG characteristic folds
and thus may belong to IgG superfamily. Further, we studied the binding
efficacy of various antiviral drugs against the modelled ORF8 of
SARS-CoV-2 (mORF8) to repurpose the drug and to use them as a probe to
study its function by studying the binding/active sites interaction.
Remdesivir had the highest binding affinity to ORF8 protein of
SARS-CoV-2. The high affinity of the adenosine analogue yields critical
information about the non-canonical RNA dependent RNA polymerase (RdRp)
function of ORF8 protein. We hypothesize that the ORF8 protein may be a
non-canonical RdRp in SARS-CoV-2 with ability to bind to canonical nsp12
complex.