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 towards RdRp. Compound 12 was found to possess a similar binding affinity as remdesivir with comparable 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.

中文翻译：

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肽核酸 (PNA) 启发的针对 COVID-19 的新型核苷酸支架的设计和计算机筛选。

简介 2019 年 12 月新型冠状病毒 COVID-19 的爆发已演变成一场大流行，危及许多人的生命。病原体是久负盛名的冠状病毒科成员 SARS-CoV-2，是一种正链单链包膜病毒，与 SARS-CoV 密切相关。了解这种疾病的病理生理学已成为当务之急，以便可以生产药物、疫苗、治疗方案和合理的治疗剂。方法 在这方面，最近的研究发现，SARS-CoV-2 的病毒基因组编码非结构蛋白，如 RNA 依赖性 RNA 聚合酶 (RdRp)，这是其转录和复制过程的重要工具。大量基于核酸的抗病毒药物被重新用于治疗靶向 RdRp 的 COVID-19。其中很少有人处于临床试验的后期阶段，包括瑞德西韦。在对大量基于核酸的药物进行详细调查时，我们惊讶地发现合成核酸骨架的探索很少或很少见。结果 我们设计了衍生自肽核酸 (PNA) 的支架，并对其进行了系统的计算机筛选。这些设计的分子已显示出对 RdRp 的出色结合。发现化合物 12 具有与瑞德西韦相似的结合亲和力和相当的药代动力学。然而，计算机毒性预测表明，化合物 12 可能是一种优越的分子，由于其优异的安全性，其 LD50 为 12,000mg/kg，而不是瑞德西韦 (LD50 =1000mg/kg)，因此可以进一步探索。