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Published on: January 7, 2022
Inhibiting the interaction between the mitochondrial receptor Tom70 and SARS CoV 2 Orf9b with small molecules.
C J San Felipe1, Kliment A Verba2, Nevan J Krogan1,3
1Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, United States.
Biorxiv : the Preprint Server for Biology
|May 7, 2026
Summary
Researchers identified two strategies to disrupt the SARS-CoV-2 Orf9b protein
Area of Science:
- Virology
- Molecular Biology
- Immunology
Background:
- SARS-CoV-2 Orf9b protein interacts with host Tom70.
- This interaction suppresses the host's Type-1 interferon response.
- Orf9b exists in a monomer-dimer equilibrium influencing Tom70 binding.
Purpose of the Study:
- To develop small molecules targeting the Orf9b-Tom70 interaction.
- To explore strategies for restoring interferon signaling against SARS-CoV-2.
Main Methods:
- Crystallographic fragment screening of Orf9b homodimer.
- High-throughput fluorescence polarization screening for Tom70:Orf9b interaction inhibitors.
Main Results:
- Identified Orf9b dimer interface binding sites for potential inhibitors.
- Functionalized fragments stabilized the Orf9b dimer, inhibiting Tom70 binding.
- Discovered separate small molecules competitively inhibiting Tom70:Orf9b interaction.
Conclusions:
- Demonstrated feasibility of targeting Orf9b-Tom70 equilibrium.
- Two distinct chemical strategies can modulate this critical viral-host interaction.
- Potential for restoring antiviral response to SARS-CoV-2 infection.
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