The COVID-19 pandemic caused by
SARS-CoV-2 has caused millions of
infections and deaths worldwide. Limited
treatment options and the threat from emerging variants underline the need for novel and widely accessible
therapeutics.
G-quadruplexes (G4s) are
nucleic acid secondary structures known to
affect many cellular processes including
viral replication and transcription. We identified heretofore not reported G4s with remarkably low
mutation frequency across >5 million
SARS-CoV-2 genomes. The G4 structure was targeted using FDA-approved
drugs that can bind G4s -
Chlorpromazine (CPZ) and
Prochlorperazine (PCZ). We found significant inhibition in
lung pathology and
lung viral load of
SARS-CoV-2 challenged
hamsters when treated with CPZ, PCZ that was comparable to the widely used
antiviral drug Remdesivir. In support,
in vitro G4 binding, inhibition of
reverse transcription from
RNA isolated from COVID-infected
humans, and attenuated
viral replication and infectivity in
Vero cell cultures were clear in case of both CPZ/PCZ. Apart from the wide accessibility of CPZ/PCZ, targeting relatively invariant
nucleic acid structures poses an attractive strategy against fast mutating
viruses like
SARS-CoV-2.