Introduction:
The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned itself
into a pandemic taking a heavy toll on human lives. The causal agent being SARS-CoV-2, a member of the
long-known Coronaviridae family, is a positive sense single-stranded enveloped virus and quite closely related to
SARS-CoV. It has become the need of the hour to understand the pathophysiology of this disease, so that drugs,
vaccines, treatment regimens and plausible therapeutic agents can be produced.
Methods:
In this regard, recent studies uncovered the fact that the viral genome of SARS-CoV-2 encodes nonstructural proteins like RNA dependent RNA polymerase (RdRp) which is an important tool for its transcription
and replication process. A large number of nucleic acid based anti-viral drugs are being repurposed for treating
COVID-19 targeting RdRp. Few of them are in the advanced stage of clinical trials including Remdesivir. While
performing close investigation of the large set of nucleic acid based drugs, we were surprised to find that the
synthetic nucleic acid backbone is explored very little or rare.
Results:
We have designed scaffolds derived from peptide nucleic acid (PNA) and subjected them for in-silico
screening systematically. These designed molecules have demonstrated excellent binding towards RdRp.
Compound 12 was found to possess similar binding affinity as Remdesivir with comparable pharmacokinetics.
However, the in-silico toxicity prediction indicates compound 12 may be a superior molecule which can be
explored further due to its excellent safety-profile with LD50 (12,000mg/kg) as opposed to Remdesivir (LD50
=1000mg/kg).
Conclusion:
Compound 12 falls in the safe category of class 6. Synthetic feasibility, equipotent binding and
very low toxicity of this peptide nucleic acid derived compounds can serve as a leading scaffold to design,
synthesize and evaluate many of similar compounds for the treatment of COVID-19.
A Peptide-Nucleic Acid Targeting miR-335-5p Enhances Expression of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Gene with the Possible Involvement of the CFTR Scaffolding Protein NHERF1