Drug Repurposing Strategies for SARS-CoV-2 Therapeutics

Drug repurposing has emerged as a cornerstone of the rapid response to the COVID-19 pandemic, offering the prospect of shortened development timelines and established safety profiles. Strategies span phenotypic screening of approved‐drug libraries, computational network-based inference of drug–target relationships and mechanistic interrogation of host–virus interactions. High‐throughput cell‐based assays have revealed unexpected antiviral activity among diverse chemical classes, while integrative systems-biology platforms map the SARS-CoV-2–host interactome to prioritise candidates that perturb essential viral life-cycle pathways. Combination therapies exploit complementary modes of action to enhance potency and mitigate resistance. Throughout these efforts, translational challenges such as off-target toxicity, misleading assay artefacts and tissue‐specific pharmacokinetics have underscored the need for rigorous in vitro–in vivo validation and pharmacometric optimisation. Collectively, repurposing efforts illustrate a globally coordinated endeavour to leverage existing pharmacopoeias in order to curb viral transmission, reduce disease severity and inform preparedness for future coronavirus outbreaks.

Research from Nature Portfolio

In intensive cell-based screening of a library of over 1,500 approved drugs, investigators identified around ninety compounds that inhibited SARS-CoV-2 replication at micromolar concentrations. These hits spanned macrolide antibiotics, proton-pump inhibitors, antiarrhythmic agents and central-nervous-system drugs, with detailed EC₅₀ and CC₅₀ determinations enabling prioritisation of eleven candidates for further in vivo evaluation. The study provided a chemical taxonomy of repurposed antivirals and underscored the importance of secondary assays to exclude cytotoxic confounders. A complementary systems-medicine approach introduced an interactive platform that integrates virus–human protein interactions, human protein–protein networks and drug-target data. Through network-based algorithms, the platform allows visual exploration of the viral interactome and predicts repurposing candidates by measuring the proximity of drug targets to key virus-perturbed host modules. This resource has accelerated hypothesis-driven selection of therapeutics and offers a mechanistic rationale for host-directed antiviral strategies.

Drug Repurposing Strategies for SARS-CoV-2 Therapeutics publication trend

The graph below shows the total number of articles in drug repurposing strategies for sars-cov-2 therapeutics across all publications each year (not limited to Nature Index journals).

Technical terms

Drug repurposing: The identification of new therapeutic uses for existing drugs outside their original medicinal indication.

Phenotypic screening: Experimental testing of compound libraries in cell-based assays to observe biological effects without presupposing specific molecular targets.

Network medicine: A computational framework that integrates biological interaction networks to predict disease-gene and drug-target relationships.

EC₅₀ (half-maximal effective concentration): The concentration of a compound at which 50% of its maximal antiviral effect is observed in vitro.

Protein–protein interaction network: A representation of the physical or functional interactions among proteins within a cell or organism.

References

1. In vitro screening of a FDA approved chemical library reveals potential inhibitors of SARS-CoV-2 replication. Scientific Reports (2020).
2. Exploring the SARS-CoV-2 virus-host-drug interactome for drug repurposing. Nature Communications (2020).
3. Antiviral effects and tissue exposure of tetrandrine against SARS‐CoV‐2 infection and COVID‐19. MedComm (2023).
4. Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment. iScience (2021).
5. Network medicine framework for identifying drug-repurposing opportunities for COVID-19. Proceedings of the National Academy of Sciences of the United States of America (2021).