ArticleScientific reports2022
Reengineering the specificity of the highly selective Clostridium botulinum protease via directed evolution.
Article in Scientific reports, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 12 citations in OpenAlex.
- Evolution of botulinum neurotoxin serotype X proteases to induce inflammatory cell death in cancer cells.Nature biotechnology · 2026Article
- Characterisation of the SNAP-25 and SNAP-23 cleavage properties of the botulinum neurotoxin-like protein from Enterococcus.Journal of neural transmission (Vienna, Austria : 1996) · 2026Article
- Probing the properties of PTEN specific botulinum toxin type E mutants.Journal of neural transmission (Vienna, Austria : 1996) · 2025Article
- Protease engineering: Approaches, tools, and emerging trends.Biotechnology advances · 2025Review
- Data-driven protease engineering by DNA-recording and epistasis-aware machine learning.Nature communications · 2025Article
- Targeted degradation of α-Synuclein using an evolved botulinum toxin protease.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Machine-learning-guided Directed Evolution for AAV Capsid Engineering.Current pharmaceutical design · 2024Review
- Making the cut with protease engineering.Cell chemical biology · 2022Review
Corrections and comments
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Authors and funding
19 authors at 3 institutions in 1 country.
Funding
Abstract
The botulinum neurotoxin serotype A (BoNT/A) cuts a single peptide bond in SNAP25, an activity used to treat a wide range of diseases. Reengineering the substrate specificity of BoNT/A's protease domain (LC/A) could expand its therapeutic applications; however, LC/A's extended substrate recognition (≈ 60 residues) challenges conventional approaches. We report a directed evolution method for retargeting LC/A and retaining its exquisite specificity. The resultant eight-mutation LC/A (omLC/A) has improved cleavage specificity and catalytic efficiency (1300- and 120-fold, respectively) for SNAP23 versus SNAP25 compared to a previously reported LC/A variant. Importantly, the BoNT/A holotoxin equipped with omLC/A retains its ability to form full-length holotoxin, infiltrate neurons, and cleave SNAP23. The identification of substrate control loops outside BoNT/A's active site could guide the design of improved BoNT proteases and inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.