State Key Laboratory of Toxicology and Medical Countermeasures, Institute of Pharmacology and Toxicology, Military Academy of Medical Sciences, Beijing, China.
Pharmacol Res Perspect. 2017 Oct;5(5). doi: 10.1002/prp2.334.
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 values of arginine-rich TAT (27.244 mg kg ) and CTP (21.345 mg kg ) 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 value (16.5 mg kg ) 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.
穿膜肽（MPP），如十一肽 TAT（YGRKKRRQRRR）和 CTP（YGRRARRRRRRR），因其能够将各种低膜通透性的物质递送到体外和体内而备受关注。我们已经成功地使用 MPP 将各种蛋白质通过血脑屏障（BBB），用于治疗多种神经疾病。然而，人们总是关注缀合物穿过 BBB 的渗透效率和机制，而忽略了穿膜肽本身的毒性。当我们给小鼠静脉注射了一定量的γ-氨基丁酸-MPP（GABA-MPP）时，令我们非常惊讶的是，小鼠在几秒钟内就出现了抽搐并死亡，而 GABA 对照小鼠则安然无恙。因此，MPP 及其缀合物的毒性的重要性开始进入我们的视野。精氨酸丰富的 TAT（27.244mg/kg）和 CTP（21.345mg/kg）本身在小鼠中的低 LD 值表明它们都属于高度毒性的化学物质。在精氨酸丰富的肽中，由纯精氨酸残基组成的 R11（RRRRRRRRRRR）具有最低的 LD 值（16.5mg/kg），表现出最高的毒性，而不含精氨酸残基的 TD（ACSSSPSKHCG）在小鼠中表现出较低的毒性和较高的存活率。缀合物中精氨酸丰富的 MPP 的质量百分比非常重要，MPP 中精氨酸的质量比与毒性呈线性相关。因此，我们得出结论，精氨酸丰富的 MPP 更适合用于大分子缀合物，而不适合用于小分子缀合物。
