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.
:
The most common reason behind dementia is Alzheimer’s disease (AD) and it is predicted to be the third lifethreatening disease apart from stroke and cancer for the geriatric population. Till now only four drugs are available in the
market for symptomatic relief. The complex nature of disease pathophysiology and lack of concrete evidences of molecular
targets are the major hurdles for developing new drug to treat AD. The the rate of attrition of many advanced drugs at clinical stages, makes the de novo discovery process very expensive. Alternatively, Drug Repurposing (DR) is an attractive tool
to develop drugs for AD in a less tedious and economic way. Therefore, continuous efforts are being made to develop a
new drug for AD by repursing old drugs through screening and data mining. For example, the survey in the drug pipeline for
Phase III clinical trials (till February 2019) which has 27 candidates, and around half of the number are drugs which have already been approved for other indications.
Although in the past the drug repurposing process for AD has been reviewed in the context of disease areas, molecular targets, there is no systematic review of repurposed drugs for AD from the recent drug development pipeline (2019-2020). In
this manuscript, we are reviewing the clinical candidates for AD with emphasis on their development history including molecular targets and the relevance of the target for AD.
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