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Targeting SARS-CoV-2 Non-Structural Proteins: A Blueprint for Next-Generation Small-Molecule Coronavirus Antivirals
Exequiel O J Porta1, Dana F AlKharboush1,2, Lauren Jackson1
1UCL School of Pharmacy, University College London, London WC1N 1AX, UK.
Pharmaceutics
|June 26, 2026
Summary
SARS-CoV-2 non-structural proteins are key targets for antiviral drugs. This review assesses these proteins for developing next-generation, broad-spectrum coronavirus therapies with improved resistance resilience.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- SARS-CoV-2 non-structural proteins are validated targets for antiviral drug development.
- Inhibitors of Mpro and RdRp set benchmarks for antiviral therapies.
- Emerging targets include PLpro, Nsp14, Nsp16, Nsp13, and Nsp15.
Purpose of the Study:
- To comprehensively assess SARS-CoV-2 non-structural proteins for drug discovery.
- To evaluate targets based on medicinal chemistry and translational potential.
- To identify opportunities for next-generation antiviral therapies and combination regimens.
Main Methods:
- Medicinal chemistry and translational assessment of non-structural proteins.
- Emphasis on structural tractability, mechanism of action, and chemical matter.
- Evaluation of cellular and in vivo antiviral evidence, conservation, resistance, and developability.
Main Results:
- First-generation inhibitors target Mpro and RdRp.
- Second-wave targets like PLpro, Nsp14, Nsp16, Nsp13, and Nsp15 show translational promise.
- Nsp1 and Nsp3 Mac1 domain are in earlier stages of chemical validation.
Conclusions:
- The non-structural proteome provides a strong foundation for next-generation antivirals.
- Focus on actionable leads and combination regimens beyond protease/polymerase inhibitors.
- Development of broader-spectrum antivirals with enhanced resilience to viral evolution is feasible.
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