A unique mid-sequence linker used to multimerize the lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1.
A unique mid-sequence linker used to multimerize the lipid-phosphatidylserine (PS) binding peptide-peptoid hybrid PPS1.
复制标题
一种独特的中序列接头，用于多聚脂质-磷脂酰丝氨酸 (PS) 结合肽-类肽杂合体 PPS1。
DOI：
10.1016/j.ejmech.2017.05.040
复制
发表时间：
2017
影响因子：
6.7
通讯作者：
Udugamasooriya,DGomika
中科院分区：
文献类型：
--
作者：
Shukla,SatyaPrakash;Manarang,JosephC;Udugamasooriya,DGomika
配体多聚体通过亲和力效应增强与细胞表面生物标记物的结合亲和力。典型的连接子从一端(例如，肽的C-端或N-端)连接单个单体配体部分，并专门针对蛋白质受体。脂质磷脂酰丝氨酸(PS)通常存在于真核细胞膜的细胞质一侧，但在肿瘤和肿瘤内皮细胞中，这种带负电荷的PS反转到外层。我们最近报道了一种PS结合肽-类肽杂交体(PPS1)，它具有明显的正电荷和疏水残基区域。PPS1单体是非活性的，当C-末端二聚(PPS1D1)时，它会触发细胞毒性。在本研究中，通过将连接子从C-末端切换到内部位置，合成了一系列独特的PPS1多聚体衍生物。利用来自C-末端的不重要的第四个残基(N-Lys)来构建连接子。该合成策略是利用(I)接头大小、(Ii)带正电残基的数量和(Iii)疏水区域数量的变化来开发的。这些新的衍生物对HCC4017肺癌细胞的细胞毒性表明，至少两个疏水区对于保持活性是重要的，并且最短的接头长度是活性的最佳。
Ligand multimerizations enhance the binding affinity towards cell surface biomarkers through their avidity effects. Typical linkers connect individual monomeric ligand moieties from one end (e.g., C- or N-terminus of a peptide) and exclusively target protein receptors. The lipid phosphatidylserine (PS) is normally present on the cytoplasmic side of the eukaryotic cell membrane, but in tumors and tumor endothelial cells, this negatively charged PS flips to the outer layer. We recently reported a PS binding peptide-peptoid hybrid (PPS1) that has distinct positively charged and hydrophobic residue-containing regions. The PPS1 monomer is inactive, and upon C-terminal dimerization (PPS1D1), it triggers cytotoxicity. In the current study, a unique series of PPS1 multimeric derivatives were synthesized by switching the linker from the C-terminus to an internal position. The unimportant fourth residue (N-lys) from the C-terminus was utilized to build the linker. The synthesis strategy was developed employing variations of (I) the linker size, (II) the number of positively charged residues, and (III) the number of hydrophobic regions. Cytotoxicity of these new derivatives on HCC4017 lung cancer cells showed that a minimum of two hydrophobic regions was important to retain the activity and that the shortest linker length was optimal for activity.