Identification of the minimum pharmacophore of lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1D1.
Identification of the minimum pharmacophore of lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1D1.
复制标题
脂质-磷脂酰丝氨酸 (PS) 结合肽-类肽杂合体 PPS1D1 的最小药效团的鉴定。
DOI：
10.1016/j.bmc.2016.07.045
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发表时间：
2016
影响因子：
3.5
通讯作者：
Udugamasooriya,DGomika
中科院分区：
文献类型：
--
作者：
Singh,Jaspal;Shukla,SatyaPrakash;Desai,TanviJ;Udugamasooriya,DGomika
我们之前报道了一种独特的多肽-类肽杂交物PPS1，它能特异性识别细胞膜上的脂磷脂-磷脂酰丝氨酸(PS)和其他一些带负电荷的磷脂，但不识别中性磷脂。PPS1的二聚体版本，即PPS1D1，可触发强大的癌细胞杀伤作用，并已在体外和体内肺癌模型中得到验证。鉴于PS和其他带负电荷的磷脂在几乎所有的肿瘤微环境中都很丰富，PPS1D1是一种有吸引力的药物先导，可以开发成一种全球适用的抗癌药物。因此，确定PPS1D1的最低药效团是非常重要的。在本研究中，我们合成了PPS1D1的丙氨酸/肌氨酸衍生物以及截断的衍生物。采用类ELISA竞争结合实验评价PS识别能力，标准MTS细胞活性实验验证这些衍生物对肺癌细胞的细胞毒作用。我们的研究表明，第二和第三位的正电荷残基以及第五到第八位的四个疏水残基对于PPS1D1的结合和活性是必不可少的。第一位的蛋氨酸不是必需的，而第四位的带正电荷的Nlys是最不需要的，因为合成的两个取代这个残基的衍生物几乎和PPS1D1一样有活性。
We previously reported a unique peptide–peptoid hybrid, PPS1 that specifically recognizes lipid–phosphatidylserine (PS) and a few other negatively charged phospholipids, but not neutral phospholipids, on the cell membrane. The dimeric version of PPS1, i.e., PPS1D1 triggers strong cancer cell cytotoxicity and has been validated in lung cancer models both in vitro and in vivo. Given that PS and other negatively charged phospholipids are abundant in almost all tumor microenvironments, PPS1D1 is an attractive drug lead that can be developed into a globally applicable anti-cancer agent. Therefore, it is extremely important to identify the minimum pharmacophore of PPS1D1. In this study, we have synthesized alanine/sarcosine derivatives as well as truncated derivatives of PPS1D1. We performed ELISA-like competitive binding assay to evaluate the PS-recognition potential and standard MTS cell viability assay on HCC4017 lung cancer cells to validate the cell cytotoxicity effects of these derivatives. Our studies indicate that positively charged residues at the second and third positions, as well as four hydrophobic residues at the fifth through eighth positions, are imperative for the binding and activity of PPS1D1. Methionine at the first position was not essential, whereas the positively charged Nlys at the fourth position was minimally needed, as two derivatives that were synthesized replacing this residue were almost as active as PPS1D1.