Design and In-silico Screening of Peptide Nucleic Acid (PNA) Inspired Novel Pronucleotide Scaffolds Targeting COVID-19

Introduction: The outburst of the novel coronavirus COVID-19, at the end of December 2019 has turned into a pandemic, risking many 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 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 non-structural 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 at the advanced stage of clinical trials, including remdesivir. While performing a detailed investigation of the large set of nucleic acid-based drugs, we were surprised to find that the synthetic nucleic acid backbone has been explored very little or rare. Results: We designed scaffolds derived from peptide nucleic acid (PNA) and subjected them to in-silico screening systematically. These designed molecules have demonstrated excellent binding to wards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with com- parable pharmacokinetics. However, the in-silico toxicity prediction indicates that 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 compound can make it a leading scaffold to design, synthesize and evaluate many similar compounds for the treatment of COVID-19.

Automated summary

This study designed scaffolds derived from peptide nucleic acid (PNA) and conducted in-silico screening to identify a compound with similar binding affinity to RdRp. Compound 12 showed comparable pharmacokinetics to remdesivir but with significantly lower toxicity, making it a potential candidate for the treatment of COVID-19.