Chlorotoxin
Chlorotoxin is a 36-amino acid peptide from deathstalker scorpion venom that binds specifically to glioma cells and matrix metalloproteinase-2, used as a tumor imaging agent.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | C158H249N51O47S8 |
| Molecular Weight | 3995.41 g/mol |
| CAS Number | 163515-35-3 |
| IUPAC Name | Chlorotoxin (Leiurus quinquestriatus) |
| Peptide Class | Scorpion Neurotoxin |
| Origin | Leiurus quinquestriatus (deathstalker) |
| Disulfide Bonds | 4 |
Structure
Chlorotoxin (CTX) is a 36-amino acid peptide from the venom of the deathstalker scorpion (Leiurus quinquestriatus). It contains four intramolecular disulfide bonds stabilizing a compact structure with an alpha-helix and a two-stranded antiparallel beta-sheet. The peptide has a net positive charge (+6) and is remarkably stable under physiological conditions due to the extensive disulfide cross-linking.
Mechanism of Action
Chlorotoxin has multiple molecular targets:
- Chloride channel block: Originally identified as a blocker of small-conductance chloride channels (ClC-3)
- MMP-2 binding: Binds matrix metalloproteinase-2 (MMP-2) on the surface of glioma cells, inhibiting enzymatic activity and invasion
- Annexin A2: Interacts with annexin A2, a protein overexpressed in many cancers
- Specificity: Binds preferentially to glioma cells over normal brain tissue, with minimal binding to normal neurons
Biological Functions
Chlorotoxin serves as a venom component for prey capture:
- Neurotoxicity: Paralyzes prey through ion channel blockade
- Anti-parasitic: Activity against parasites in the scorpion’s environment
- Tumor selectivity: Preferential binding to glioma and other cancer cells overexpressing MMP-2
Research and Clinical Applications
- TM-601 (Tozuleristide): Synthetic chlorotoxin conjugated to iodine-131 for targeted radiotherapy of glioma
- Tumor imaging: Fluorescent chlorotoxin (BLZ-100/Tozuleristide) for intraoperative tumor visualization in clinical trials
- Drug delivery: Chlorotoxin-conjugated nanoparticles for targeted delivery of chemotherapeutics to glioma
- Research tool: Mapping chloride channel distribution in tissues
Safety and Side Effects
Native chlorotoxin causes neurotoxicity when injected systemically (lethal dose in mice ~4 mg/kg). Therapeutic derivatives use low doses and targeted delivery. TM-601 has shown acceptable safety profiles in Phase I/II clinical trials for glioma. Fluorescent chlorotoxin for imaging uses nanomolar concentrations with minimal toxicity.
References
- Lyons, S.A., et al. (2002). Chlorotoxin, a scorpion-derived peptide, specifically binds to gliomas and tumors of neuroectodermal origin. Glia, 39, 162-173.
- Veiseh, M., et al. (2007). Chlorotoxin bound to squalene nanoparticles for targeted delivery to gliomas. Cancer Research, 67, 6882-6888.
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