ArticleThe Journal of biological chemistry2011
Basic tetrapeptides as potent intracellular inhibitors of type A botulinum neurotoxin protease activity.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 29 citations in OpenAlex.
- A novel RRGW derived peptide is a promising inhibitor of BoNT/A.Journal of enzyme inhibition and medicinal chemistry · 2023Article
- Dock-able linear and homodetic di, tri, tetra and pentapeptide library from canonical amino acids: SARS-CoV-2 Mpro as a case study.Journal of pharmaceutical analysis · 2023Article
- Recent developments in cell-based assays and stem cell technologies for botulinum neurotoxin research and drug discovery.Expert review of molecular diagnostics · 2014Review
- Cleavage of SNAP25 and its shorter versions by the protease domain of serotype A botulinum neurotoxin.PloS one · 2014Article
- Cargo-delivery platforms for targeted delivery of inhibitor cargos against botulism.Current topics in medicinal chemistry · 2014Review
- The C terminus of the catalytic domain of type A botulinum neurotoxin may facilitate product release from the active site.The Journal of biological chemistry · 2013Article
- Structural framework for covalent inhibition of Clostridium botulinum neurotoxin A by targeting Cys165.The Journal of biological chemistry · 2012Article
- Glycine insertion at protease cleavage site of SNAP25 resists cleavage but enhances affinity for botulinum neurotoxin serotype A.Protein science : a publication of the Protein Society · 2012Article
- Inhibition of catalytic activities of botulinum neurotoxin light chains of serotypes A, B and E by acetate, sulfate and calcium.International journal of biochemistry and molecular biology · 2012Article
- Tyrosine phosphorylation of botulinum neurotoxin protease domains.Frontiers in pharmacology · 2012Article
Corrections and comments
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Authors and funding
4 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Botulinum neurotoxins (BoNT) are the most potent of all toxins that cause flaccid muscle paralysis leading to death. They are also potential biothreat agents. A systematic investigation of various short peptide inhibitors of the BoNT protease domain with a 17-residue peptide substrate led to arginine-arginine-glycine-cysteine having a basic tetrapeptide structure as the most potent inhibitor. When assayed in the presence of dithiothreitol (DTT), the inhibitory effect was drastically reduced. Replacing the terminal cysteine with one hydrophobic residue eliminated the DTT effect but with two hydrophobic residues made the pentapeptide a poor inhibitor. Replacing the first arginine with cysteine or adding an additional cysteine at the N terminus did not improve inhibition. When assessed using mouse brain lysates, the tetrapeptides also inhibited BoNT/A cleavage of the endogenous SNAP-25. The peptides penetrated the neuronal cell lines, N2A and BE(2)-M17, without adversely affecting metabolic functions as measured by ATP production and P-38 phosphorylation. Biological activity of the peptides persisted within cultured chick motor neurons and rat and mouse cerebellar neurons for more than 40 h and inhibited BoNT/A protease action inside the neurons in a dose- and time-dependent fashion. Our results define a tetrapeptide as the smallest peptide inhibitor in the backdrop of a large substrate protein of 200+ amino acids having multiple interaction regions with its cognate enzyme. The inhibitors should also be valuable candidates for drug development.
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