Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells,RSC Chemical Biology

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Cyclic peptide scaffold with ability to stabilize and deliver a helical cell-impermeable cargo across membranes of cultured cancer cells
RSC Chemical Biology ( IF 4.2 ) Pub Date : 2020-10-20 , DOI: 10.1039/d0cb00099j
Nicole Lawrence ₁ , Grégoire J-B Philippe ₁ , Peta J Harvey ₁ , Nicholas D Condon ₁ , Aurélie H Benfield _{1,

2} , Olivier Cheneval ₁ , David J Craik ₁ , Sónia Troeira Henriques _{1,

2}

Affiliation

Cell penetrating peptides (CPPs) are valuable tools for developing anticancer therapies due to their ability to access intracellular targets, including protein–protein interactions. cPF4PD is a newly described CPP designed from a transduction domain of the human defense protein platelet factor 4 (PF4), that also has antimalarial activity. The cPF4PD peptide recapitulates the helical structure of the PF4 domain and maintains activity against intracellular malaria parasites via a selective membrane-active mechanism. We hypothesized that cPF4PD and PF4-derived peptide analogues would enter cancer cells and have utility as scaffolds for delivering a peptide dual inhibitor (pDI) sequence with ability to inhibit p53:MDM2/X interactions and reactivate the p53 pathway. Here we designed and produced PF4 peptide and PF4 peptide-pDI grafted analogues with low micromolar activity toward melanoma and leukemia. Two grafted analogues achieved a stable helical structure and inhibited interaction with MDM2 and MDMX. These peptides reached the cytoplasm of cells but were unable to reactivate the p53 pathway. Instead, the cytotoxic mechanism was attributed to peptide binding to mitochondrial membranes that perturbed function within two hours of treatment. These studies of PF4-derived CPPs suggest their potential as scaffolds for delivering cell-impermeable cargoes into the cytoplasm of cells and highlight the importance of characterizing the internalization and cell death mechanism of designer peptide-based drugs.

中文翻译：

环状肽支架能够稳定并传递螺旋细胞不可渗透的货物穿过培养的癌细胞膜

细胞穿透肽 (CPP) 是开发抗癌疗法的重要工具，因为它们能够进入细胞内靶标，包括蛋白质-蛋白质相互作用。cPF4PD 是一种新描述的 CPP，由人类防御蛋白血小板因子 4 (PF4) 的转导结构域设计，也具有抗疟活性。所述cPF4PD肽概括了PF4域的螺旋结构，并保持活动针对细胞内疟原虫经由选择性的膜活性机制。我们假设 cPF4PD 和 PF4 衍生的肽类似物将进入癌细胞并作为支架用于递送具有抑制 p53:MDM2/X 相互作用和重新激活 p53 通路能力的肽双重抑制剂 (pDI) 序列。在这里，我们设计并生产了对黑色素瘤和白血病具有低微摩尔活性的 PF4 肽和 PF4 肽-pDI 嫁接类似物。两个接枝类似物实现了稳定的螺旋结构并抑制了与 MDM2 和 MDMX 的相互作用。这些肽到达细胞的细胞质，但无法重新激活 p53 通路。相反，细胞毒性机制归因于肽与线粒体膜结合，在治疗后两小时内扰乱功能。

更新日期：2020-11-03

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