Arginine-rich membrane-permeable peptides are seriously toxic
Qian Li1, Mengchuan Xu1, Yali Cui1
1State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Military Academy of Medical Sciences, Beijing, China.
Pharmacology Research & Perspectives
|October 4, 2017
Summary
Membrane-permeable peptides (MPPs) like TAT and CTP show high toxicity, especially arginine-rich ones. Their arginine content correlates with toxicity, making them better for large molecule delivery than small ones.
Area of Science:
- Biochemistry
- Pharmacology
- Neuroscience
Background:
- Membrane-permeable peptides (MPPs) are crucial for delivering low-permeability materials across biological barriers like the blood-brain barrier (BBB).
- MPPs like TAT and CTP have shown promise in delivering proteins for treating neurological diseases.
- The potential toxicity of MPPs themselves has been largely overlooked despite their widespread use.
Purpose of the Study:
- To investigate the inherent toxicity of various membrane-permeable peptides (MPPs).
- To determine the correlation between MPP structure, particularly arginine content, and toxicity.
- To assess the suitability of arginine-rich MPPs for delivering small versus macro-molecular conjugates.
Main Methods:
- Administered varying doses of gamma-aminobutyric acid-MPP (GABA-MPP), TAT, CTP, R11, and TD to mice via intravenous injection.
- Monitored survival rates and observed toxicological effects, including seizures.
- Determined LD50 values for different arginine-rich and arginine-free MPPs.
Main Results:
- Intravenous injection of GABA-MPP caused rapid death with seizures in mice, while GABA controls survived.
- Arginine-rich MPPs like TAT (LD50 = 27.244 mg/kg), CTP (LD50 = 21.345 mg/kg), and R11 (LD50 = 16.5 mg/kg) exhibited significant toxicity.
- R11, a purely arginine peptide, demonstrated the highest toxicity, whereas the arginine-free peptide TD showed much lower toxicity.
- A linear correlation was observed between the mass percentage of arginine in MPPs and their toxicity.
Conclusions:
- Arginine-rich MPPs possess inherent toxicity, with toxicity directly correlating to arginine content.
- MPPs with high arginine content are more suitable for delivering macro-molecular conjugates than small-molecular ones.
- Further research into MPP toxicity is essential for safe and effective therapeutic applications.
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