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Updated: Dec 22, 2025
Pharmacophore Modeling for Targets with Extensive Ligand Libraries: A Case Study on SARS-CoV-2 Mpro
Published on: September 26, 2025
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
David E Gordon1,2,3,4, Gwendolyn M Jang1,2,3,4, Mehdi Bouhaddou1,2,3,4
1QBI COVID-19 Research Group (QCRG), San Francisco, CA, USA.
Abstract:
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein-protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Insights
Researchers identified 332 protein-protein interactions between SARS-CoV-2 and human cells. They found 69 compounds targeting 66 druggable human proteins, with two drug types showing antiviral activity against COVID-19.
Area of Science:
- Virology
- Molecular Biology
- Drug Discovery
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a global pandemic with no approved treatments or vaccines.
- Understanding SARS-CoV-2's cellular infection mechanisms is crucial for developing effective therapies.
Purpose of the Study:
- To identify host-pathogen interactions between SARS-CoV-2 and human proteins.
- To discover potential drug targets and antiviral compounds for COVID-19 treatment.
Main Methods:
- Cloned, tagged, and expressed 26 SARS-CoV-2 proteins in human cells.
- Utilized affinity-purification mass spectrometry to identify protein-protein interactions.
- Screened identified compounds for antiviral activity in viral assays.
Main Results:
- Identified 332 high-confidence SARS-CoV-2-human protein-protein interactions.
- Found 66 druggable human proteins targeted by 69 compounds, including FDA-approved drugs.
- Discovered antiviral activity in mRNA translation inhibitors and sigma receptor modulators.
Conclusions:
- Host-targeting agents show promise for COVID-19 therapy.
- Combination therapies involving host-factor-targeting agents could be a viable treatment strategy.
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