Transformation of the naturally occurring frog skin peptide, alyteserin-2a into a potent, non-toxic anti-cancer agent
Transformation of the naturally occurring frog skin peptide, alyteserin-2a into a potent, non-toxic anti-cancer agent
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DOI：
10.1007/s00726-012-1395-7
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发表时间：
2013-02-01
期刊：
影响因子：
3.5
通讯作者：
Attoub, Samir
中科院分区：
文献类型：
--
作者：
Conlon, J. Michael;Mechkarska, Milena;Attoub, Samir
Alyteserin-2a（ILGKLLSTAAGLLSNL.NH2）是一种阳离子、两亲性α-螺旋细胞穿透肽，首先从助产士蟾蜍Alytes obstricans的皮肤分泌物中分离。通过合成alyteserin-2a的类似物来研究结构-活性关系，其中螺旋的疏水表面上的氨基酸被l-色氨酸取代，亲水表面上的氨基酸被一个或多个l-赖氨酸或d-赖氨酸残基取代。含Trp的肽显示出对非小细胞肺腺癌A549细胞的细胞毒性活性增加（高达11倍），但对人红细胞的溶血活性平行增加。N15 K类似物对A549细胞的效力（LC 50 = 13 μ M）相对于阿色林-2a增加6倍，治疗指数（红细胞和肿瘤细胞的LC 50的比率）增加2倍。将d-Lys（11）残基掺入N15 K类似物中产生了一种肽，该肽保留了对A549细胞的效力（LC 50 = 15 μ M），但其治疗指数相对于天然肽提高了13倍。[G11k[N15 K] alyteserin-2a对人肝癌HepG 2细胞（LC 50 = 26 μ M）、乳腺癌MDA-MB-231细胞（LC 50 = 20 μ M）和结肠直肠腺癌HT-29细胞（LC 50 = 28 μ M）也有活性。[G11k浓度低至1 μ g/mL的[N15 K] alyteserin-2a显著（P < 0.05）抑制免疫抑制性细胞因子IL-10和TGF-β从未刺激的和伴刀豆球蛋白A刺激的外周血单核细胞的释放。数据表明增加阳离子性同时降低天然存在的两亲性α-螺旋肽的螺旋性以产生对肿瘤细胞具有改善的细胞毒性但对非肿瘤细胞具有降低的活性的类似物的策略。
Alyteserin-2a (ILGKLLSTAAGLLSNL.NH2) is a cationic, amphipathic alpha-helical cell-penetrating peptide, first isolated from skin secretions of the midwife toad Alytes obstetricans. Structure-activity relationships were investigated by synthesizing analogs of alyteserin-2a in which amino acids on the hydrophobic face of the helix were replaced by l-tryptophan and amino acids on the hydrophilic face were replaced by one or more l-lysine or d-lysine residues. The Trp-containing peptides display increased cytotoxic activity against non-small cell lung adenocarcinoma A549 cells (up to 11-fold), but hemolytic activity against human erythrocytes increases in parallel. The potency of the N15K analog against A549 cells (LC50 = 13 mu M) increases sixfold relative to alyteserin-2a and the therapeutic index (ratio of LC50 for erythrocytes and tumor cells) increases twofold. Incorporation of a d-Lys(11) residue into the N15K analog generates a peptide that retains potency against A549 cells (LC50 = 15 mu M) but whose therapeutic index is 13-fold elevated relative to the native peptide. [G11k, N15K] alyteserin-2a is also active against human hepatocarcinoma HepG2 cells (LC50 = 26 mu M), breast adenocarcinoma MDA-MB-231 cells (LC50 = 20 mu M), and colorectal adenocarcinoma HT-29 cells (LC50 = 28 mu M). [G11k, N15K] alyteserin-2a, in concentrations as low as 1 mu g/mL, significantly (P < 0.05) inhibits the release of the immune-suppressive cytokines IL-10 and TGF-beta from unstimulated and concanavalin A-stimulated peripheral blood mononuclear cells. The data suggest a strategy of increasing the cationicity while reducing the helicity of naturally occurring amphipathic alpha-helical peptides to generate analogs with improved cytotoxicity against tumor cells but decreased activity against non-neoplastic cells.