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Published on: September 8, 2021
Minibinders targeting Staphylococcus aureus α-toxin exert protective effects in vivo
Jun Weng1, Yang Hu2, Keke Wang2
1State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China; National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of Life Sciences, Hubei University, Wuhan, Hubei 430062, China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
Computationally designed minibinders effectively neutralize Staphylococcus aureus alpha-toxin. Binder2 demonstrated potent inhibition of toxin activity and protection in a mouse model, showing promise as a novel therapeutic.
Area of Science:
- Microbiology
- Computational Biology
- Drug Discovery
Background:
- Staphylococcus aureus is a major global pathogen.
- Alpha-toxin (α-toxin) is a key virulence factor contributing to S. aureus pathogenesis.
- Targeting α-toxin is a potential therapeutic strategy.
Purpose of the Study:
- To computationally design minibinder proteins targeting α-toxin.
- To evaluate the efficacy of these minibinders in vitro and in vivo.
Main Methods:
- De novo computational design pipeline for minibinder generation.
- Expression, purification, and characterization of designed minibinders.
- In vitro assays for binding affinity, hemolytic and cytotoxic inhibition, and cytokine expression.
- In vivo studies using a murine model of α-toxin challenge.
Main Results:
- Three minibinders were successfully designed, expressed, and purified.
- Minibinders showed thermostable structures and specific binding to α-toxin, with Binder2 having the highest affinity.
- All minibinders inhibited α-toxin's hemolytic and cytotoxic effects in vitro.
- Binder2 reduced α-toxin-induced cytokine release and protected mice from lethal α-toxin challenge.
Conclusions:
- Computationally designed minibinders are effective α-toxin antagonists.
- Binder2 is a promising lead candidate for developing therapeutics against S. aureus infections.
- This study validates the potential of computational design for novel therapeutic development.
