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Reprogramming the SARS-CoV-1 Neutralizing Antibody S230 to SARS-CoV-2 via Directed Evolution and Molecular
Inji Jung1,2,3, Dinesh Kumar Sriramulu4, Sun-Gu Lee4
1Department of Biomedical Sciences, Graduate School, Korea University, Seoul 02707, Republic of Korea.
ACS Synthetic Biology
|November 14, 2025
Summary
Researchers reprogrammed a SARS-CoV-1 antibody to target SARS-CoV-2 using directed evolution and molecular docking. The modified antibody neutralized SARS-CoV-2, demonstrating a new platform for adapting antibodies to emerging pathogens.
Area of Science:
- Immunology
- Structural Biology
- Synthetic Biology
Background:
- The SARS-CoV-1 neutralizing antibody S230 lacks activity against SARS-CoV-2.
- Developing broad-spectrum neutralizing antibodies is crucial for pandemic preparedness.
Purpose of the Study:
- To reprogram the antigen specificity of the SARS-CoV-1 antibody S230 to target SARS-CoV-2.
- To investigate the molecular basis of antibody specificity reprogramming.
Main Methods:
- Constructed an error-prone single-chain variable fragment (scFv) library from S230.
- Screened the library using bacterial display against the SARS-CoV-2 receptor-binding domain (RBD).
- Utilized molecular docking and reversion analysis to understand mutation effects.
Main Results:
- Identified IJ36-V, an optimized antibody variant with efficient SARS-CoV-2 neutralization.
- IJ36-V retained cross-reactivity with SARS-CoV-1 RBD, showing extended functional breadth.
- Two specific mutations (R56W and N57Y) were found to cooperatively stabilize the binding interface.
Conclusions:
- A limited set of synergistic mutations can enable antigen recognition of related but divergent targets.
- Established a modular and evolvable platform for antibody reprogramming using synthetic biology.
- Demonstrated rapid adaptation of antibody scaffolds for emerging viral threats.
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