Arginine‐rich membrane‐permeable peptides are seriously toxic

The membrane‐permeable peptides (MPP) such as undecapeptides TAT (YGRKKRRQRRR) and CTP (YGRRARRRRRR) have been receiving much attention for delivering various kinds of low membrane‐permeability materials in vitro and in vivo. We have successfully used MPP in carrying various proteins through blood‐brain barrier (BBB) in treatment of many kinds of nervous diseases. However, people always concentrate their mind on the efficacy and the mechanism of permeation of the conjugates across BBB, but overlook the toxicity of the membrane‐permeable peptide itself. Once we injected intravenously not very large amounts of gamma‐aminobutyric acid‐MPP (GABA‐MPP) to the mice, to our great surprise, the mice died within seconds with seizure, whereas the GABA control mice well survived. Thus, the importance of the toxicity of MPPs and their conjugates comes into the field of our vision. The low LD(50) values of arginine‐rich TAT (27.244 mg kg(−1)) and CTP (21.345 mg kg(−1)) per se in mice indicate that they all fall within the range of highly toxic chemicals. Among the arginine‐rich peptides, R11 (RRRRRRRRRRR), a peptide composed purely of arginine residues, has the lowest LD(50) value (16.5 mg kg(−1)) and manifests the highest toxicity, whereas TD (ACSSSPSKHCG), a peptide without arginine residue, shows a much lower toxicity and higher survival rate in mice. The mass percentage of arginine‐rich MPP in the conjugate is critically important, the mass radio of arginine in the MPP appears a linear correlation with the toxicity. Thus we conclude, the arginine‐rich MPPs are more suitable for using in the macro‐molecular conjugates, but not in the small‐molecular one.