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Covid-19: Omics-based drug repurposing

Post by on Thursday, March 26, 2020

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Viruses are responsible for socio-economic and health issues each year worldwide, posing major threats for the populations and killing millions of people. They are the main cause of work and job losses every year. Preventive medicines are available only for the limited number of viruses.

In December 2019, the pathogenic strain of a group of coronaviruses (CoVs), HCoV, named 2019 novel coronavirus (2019-nCoV/SARS-CoV2), as the cause of coronavirus disease 2019 (abbreviated as COVID-19), was found in Wuhan, China.

As of 24 March 2020, there have been over 381,600 cases with over 16,500 deaths (WHO) for the 2019-nCoV/SARS-CoV-2 outbreak worldwide. Furthermore, human-to-human transmission has occurred among close contacts.

However, there are currently no effective medications against nCoV/SARS-CoV-2.Thus, there is an urgent need of developing antiviral drugs to control this deadly global pandemic.

Drug development research for infectious diseases has led to a number of effective therapies. The formation of drug-induced toxicity depends on the de novo prediction of how a set of small molecules or molecules will interact with a target pathogen or host protein. Such an estimate is difficult, time-consuming, and expensive.

Additional methods are needed to find new ways of treating and improving these existing ones. However, there are still many diseases for which no drugs or vaccines are available.

One promising approach is drug repurposing or repositioning; that is, applying known drugs or compounds to new indications.

Drug repurposing, represented as an effective drug discovery strategy from existing drugs, could significantly shorten the time and reduce the cost compared to de novo drug discovery and randomised clinical trial.

Although the idea is not new, past strategies rely on hypothesis-driven methods that often involve computational comparisons of a specific viral or human protein, requiring large amounts of expert knowledge on the chemical and drug target under study.

Recent developments in omics and high-throughput techniques like transcriptomics, protomics, or metabolimics have opened the door to using drug repurposing approaches that do not rely on generating empirical data related to binding characteristics or mechanism of action.

Instead, these approaches use the methods of systems biology and bioinformatics to directly compare the host response to pathogen and drug.

These approaches assist analysis of genome-wide screens that greatly enhance insights that can help in identifying fingerprint or signature of any specific cell state, including during infection or drug treatment, and screening of databases for compounds that counteract virogenomic signatures that could enable rapid identification of effective antivirals.

Along with the study of drug-induced gene signature it is feasible to take advantage of the deeper understanding of the host response that comes from network modeling which further aids in identifying the complex network of host-pathogen interactions.

It also generates a shortlist of potential gene targets from a multitude of candidates, thus setting the stage for a new era of rational identification of drug targets for host-directed antiviral therapies by quantifying the interplay between the virus-host interactome and drug targets.

This rests on the notions that the proteins that functionally associate with viral infection are localised in the corresponding subnetwork within the comprehensive human Protein Protein Interaction (PPI) network and proteins that serve as drug targets for a specific disease may also be suitable drug targets for potential antiviral infection owing to common PPIs and functional pathways elucidated by the human interactme.

Such innovative omics-based strategies are strongly supported by a shift of paradigms in drug discovery, from one-drug-one-target to one-drug-multiple-targets.

In that sense, different in silicoapproaches based on structural studies, systems biology approaches, and host gene expression analyses can been applied to decipher multi-purpose effects of many US Food and Drug Administration (FDA)-approved drugs.

Various studies using these high throughput omics-based platforms for antiviral drug development are currently being carried out by scientists around the world. Undertaking studies to perform in silico drug screening using Connectivity Map (CMAP), the Broad Institute's publicly available database of more than 7,000 drug-associated gene expression profiles and has identified a list of candidate bioactive molecules with gene signatures anti-correlated with those of the patients acute infection state.

The potential antiviral properties of selected FDA-approved molecules were validated in vitro for the treatment of viral infectious diseases of Influenza, Zika and other deadly viruses.

The recent work published by Yadi Zhou and colleagues at the Genomic Medicine Institute, Ohio, USA (Cell Discovery, March (2020) based on network based drug repurposing for 2019-nCoV/SARS-CoV-2 is being appreciated all over the world.

More such omics-based drug repurposing research works should be proposed and supported by funding agencies for the current 2019-nCoV/SARS-CoV-2 viral outbreak in order to control this deadly pandemic.

Author is a virologist

 

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