Amphipathicity Determines Different Cytotoxic Mechanisms of Lysine- or Arginine-Rich Cationic Hydrophobic Peptides in Cancer Cells
Amphipathicity Determines Different Cytotoxic Mechanisms of Lysine- or Arginine-Rich Cationic Hydrophobic Peptides in Cancer Cells
复制标题
两亲性决定癌细胞中富含赖氨酸或精氨酸的阳离子疏水肽的不同细胞毒性机制
DOI：
10.1021/acs.jmedchem.5b02016
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发表时间：
2016-06-09
影响因子：
7.3
通讯作者：
Fei, Hao
中科院分区：
文献类型：
--
作者：
Liu, Xiaoli;Cao, Rui;Fei, Hao
已知阳离子两亲性肽（CAP）能够引起膜去稳定并诱导细胞死亡，然而疏水性、两亲性和赖氨酸（K）/精氨酸（R）组成如何协同影响肽活性仍然不完全清楚。在这里，我们设计了一组肽的基础上，众所周知的抗癌肽KLA。增加疏水性增强的细胞毒性的K-和R-丰富的肽。具有完整的两亲性螺旋界面的肽可以通过膜裂解机制引起瞬时细胞死亡。有趣的是，重排残基位置以最小化两亲性导致对富K肽的细胞毒性大大降低，但对富R肽没有。两亲性最小化的富R肽6（RL 2）（RLLRLLRLRRLLRL-NH 2）穿透细胞膜并诱导caspase-3依赖的凋亡性细胞死亡。我们发现，疏水性，两亲性和K/R残基的调制导致阳离子疏水肽的不同的作用机制。两亲性降低、富含甘氨酸的阳离子疏水肽（CHP）可能代表一类新的肽治疗剂。
Cationic amphipathic peptides (CAPs) are known to be able to cause membrane destabilization and induce cell death, yet how the hydrophobicity, amphipathicity, and lysine (K)/arginine (R) composition synergistically affect the peptide activity remains incompletely understood. Here, we designed a panel of peptides based on the well-known anticancer peptide KLA. Increasing hydrophobicity enhanced the cytotoxicities of both the K- and R-rich peptides. Peptides with an intact amphipathic helical interface can cause instant cell death through a membrane lysis mechanism. Interestingly, rearranging the residue positions to minimize amphipathicity caused a great decrease of cytotoxicity to the K-rich peptides but not to the R-rich peptides. The amphipathicity-minimized R-rich peptide 6 (RL2) (RLLRLLRLRRLLRL-NH2) penetrated the cell membrane and induced caspase-3-dependent apoptotic cell death. We found that the modulation of hydrophobicity, amphipathicity, and K/R residues leads to distinct mechanisms of action of cationic hydrophobic peptides. Amphipathicity-reduced, arginine-rich cationic hydrophobic peptides (CHPs) may represent a new class of peptide therapeutics.