Selective anticancer activity of synthetic peptides derived from the host defence peptide tritrpticin.,Biochimica et Biophysica Acta (BBA) - Biomembranes

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Selective anticancer activity of synthetic peptides derived from the host defence peptide tritrpticin.
Biochimica et Biophysica Acta (BBA) - Biomembranes ( IF 2.8 ) Pub Date : 2020-02-29 , DOI: 10.1016/j.bbamem.2020.183228
Mauricio Arias ₁ , Evan F Haney ₂ , Ashley L Hilchie ₃ , Jennifer A Corcoran ₄ , M Eric Hyndman ₅ , Robert E W Hancock ₂ , Hans J Vogel ₆

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Antimicrobial peptides (AMPs) constitute a diverse family of peptides with the ability to protect their host against microbial infections. In addition to their ability to kill microorganisms, several AMPs also exhibit selective cytotoxicity towards cancer cells and are collectively referred to as anticancer peptides (ACPs). Here a large library of AMPs, mainly derived from the porcine cathelicidin peptide, tritrpticin (VRRFPWWWPFLRR), were assessed for their anticancer activity against the Jurkat T cell leukemia line. These anticancer potencies were compared to the cytotoxicity of the peptides towards normal cells isolated from healthy donors, namely peripheral blood mononuclear cells (PBMCs) and red blood cells (RBCs; where hemolytic activity was assessed). Among the active tritrpticin derivatives, substitution of Arg by Lys enhanced the selectivity of the peptides towards Jurkat cells when compared to PBMCs. Additionally, the side chain length of the Lys residues was also optimized to further enhance the tritrpticin ACP selectivity at low concentrations. The mechanism of action of the peptides with high selectivity involved the permeabilization of the cytoplasmic membrane of Jurkat cells, without formation of apoptotic bodies. The incorporation of non-natural Lys-based cationic amino acids could provide a new strategy to improve the selectivity of other synthetic ACPs to enhance their potential for therapeutic use against leukemia cells.

中文翻译：

衍生自宿主防御肽tritrpticin的合成肽的选择性抗癌活性。

抗菌肽（AMP）构成了多种肽家族，具有保护其宿主免受微生物感染的能力。除杀死微生物的能力外，几种AMP还表现出对癌细胞的选择性细胞毒性，并被统称为抗癌肽（ACP）。在这里，评估了一个主要来自于猪cathelicidin肽tritrpticin（VRRFPWWWPFLRR）的AMPs的大型文库对Jurkat T细胞白血病细胞系的抗癌活性。将这些抗癌效力与该肽对从健康供体分离的正常细胞（即外周血单核细胞（PBMC）和红细胞（RBC；评估了溶血活性）的细胞毒性）进行了比较。在活性三苯甲基吡啶衍生物中，与PBMC相比，Lys取代Arg可以增强多肽对Jurkat细胞的选择性。另外，还优化了Lys残基的侧链长度，以进一步提高低浓度下的三苯乙酸ACP选择性。具有高选择性的肽的作用机制涉及Jurkat细胞的细胞质膜的通透性，而不会形成凋亡小体。掺入非天然基于Lys的阳离子氨基酸可以提供一种提高其他合成ACP选择性的新策略，从而增强其对白血病细胞进行治疗的潜力。还优化了Lys残基的侧链长度，以进一步提高低浓度下的三苯乙酸ACP选择性。具有高选择性的肽的作用机制涉及Jurkat细胞的细胞质膜的通透性，而不会形成凋亡小体。掺入非天然基于Lys的阳离子氨基酸可以提供一种提高其他合成ACP选择性的新策略，从而增强其对白血病细胞进行治疗的潜力。还优化了Lys残基的侧链长度，以进一步提高低浓度下的三苯乙酸ACP选择性。具有高选择性的肽的作用机制涉及Jurkat细胞的细胞质膜的通透性，而不会形成凋亡小体。掺入非天然基于Lys的阳离子氨基酸可以提供一种提高其他合成ACP选择性的新策略，从而增强其对白血病细胞进行治疗的潜力。

更新日期：2020-02-29

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