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 LD50 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 LD50 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.
['Li|Qian|Q|0000-0002-3039-1896', 'Xu|Mengchuan|M|', 'Cui|Yali|Y|', 'Huang|Chunqian|C|', 'Sun|Manji|M|']
D000818:Animals D001120:Arginine D001812:Blood-Brain Barrier D002463:Cell Membrane Permeability D007275:Injections, Intravenous D007928:Lethal Dose 50 D051379:Mice D009842:Oligopeptides D010446:Peptide Fragments D010455:Peptides D013329:Structure-Activity Relationship D005680:gamma-Aminobutyric Acid D054322:tat Gene Products, Human Immunodeficiency Virus
membrane-permeable peptides arginine-rich peptides Arginine