Anti-coronoviral Drugs
Anti-coronoviral Ribozymes
Updated
Coordinates
Translate SARS s2m
crystal structure Back
to SARS-CoV-2 Project
A collaboration between the Wm. Scott and Harry Noller
Labs of the UCSC RNA
Center, Ben
Luisi's Lab at Cambridge University, and IncisiveRNA, Inc. of
Santa Cruz.
SARS-CoV-2, the virus that causes COVID-19, is a 30kb single-strand
genomic +mRNA virus. The genomic RNA possesses a 5'-UTR with a
5'-cap, and a 3'-UTR and polyA tail. The most highly conserved
sequence in the virus is the nearly invariant
s2m (stem-loop 2 motif) found
also in SARS-CoV-1, MERS-CoV, and other coronaviruses and
astroviruses. It is believed to interact with the 5'-leader
sequence and invariant TRS that is prepended onto all of the
subgenomic mRNA transcripts produced in the course of the viral
life cycle. These, along with several highly conserved but
putatively unstructured sequences in the SARS-CoV-2 genomic RNA,
thus make ideal targets for potential antiviral therapeutics that
directly target the virus's RNA. Although many potential antiviral
drugs target viral proteins such as the replicase, our approach is
complementary, in that it directly and efficiently targets the RNA
itself for cleavage and immediate destruction of the virus. Because
SARS-CoV-2 suppresses the RNAi-mediated cellular protection
mechanism via the viral N capsid protein, we employ an
RNAi-independent strategy to target and destroy the genomic
message, using
a
novel and highly-active class of hammerhead ribozymes. Based on
previously published structural and mechanistic investigations from
our lab, as well as preliminary experimental results, we have
developed a class of extremely active ribozymes to target the most
conserved and functionally important vulnerable regions of the
virus RNA. We are currently testing and optimizing these under
standard
in vitro and human cell culture conditions, with the hope
of soon identifying the most promising antiviral drug candidates
for further development.