Introduction

Bacteria and cancer cells share a common trait—both possess an electronegative surface that distinguishes them from healthy mammalian counterparts. This opens opportunities to repurpose antimicrobial peptides (AMPs), which are cationic amphiphiles that kill bacteria by disrupting their anionic cell envelope, into anticancer peptides (ACPs). To test this assertion, we investigate the mechanisms by which a pathogen-specific AMP, originally designed to kill bacterial Tuberculosis, potentiates the lytic destruction of drug-resistant cancers and synergistically enhances chemotherapeutic potency.

Materials and Methods

De novo peptide design, paired with cellular assays, elucidate structure-activity relationships (SAR) important to ACP potency and specificity. Using the sequence MAD1, microscopy, spectrophotometry and flow cytometry identify the peptide’s anticancer mechanisms, while parallel combinatorial screens define chemotherapeutic synergy in drug-resistant cell lines and patient derived ex vivo tumors.

Results

SAR investigations reveal spatial sequestration of amphiphilic regions increases ACP potency, but at the cost of specificity. Selecting MAD1 as a lead sequence, mechanistic studies identify that the peptide forms pore-like supramolecular assemblies within the plasma and nuclear membranes of cancer cells to potentiate death through lytic and apoptotic mechanisms. This diverse activity enables MAD1 to synergize broadly with chemotherapeutics, displaying remarkable combinatorial efficacy against drug-resistant ovarian carcinoma cells and patient-derived tumor spheroids.

Conclusions

We show that cancer-specific ACPs can be rationally engineered using nature’s AMP toolbox as templates. Selecting the antimicrobial peptide MAD1, we demonstrate the potential of this strategy to open a wealth of synthetic biotherapies that offer new, combinatorial opportunities against drug resistant tumors.

中文翻译：

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将抗菌肽重新设计成针对耐药性卵巢癌的溶瘤药

介绍

细菌和癌细胞有一个共同的特征——它们都具有将它们与健康的哺乳动物对应物区分开来的电负性表面。这为将抗菌肽 (AMP) 重新利用为抗癌肽 (ACP) 提供了机会，抗菌肽 (AMP) 是阳离子两亲物，通过破坏其阴离子细胞包膜来杀死细菌。为了验证这一说法，我们研究了最初设计用于杀死细菌结核病的病原体特异性 AMP 增强耐药性癌症的溶解破坏并协同增强化疗效力的机制。

材料和方法

从头肽设计与细胞分析相结合，阐明了对 ACP 效力和特异性很重要的构效关系 (SAR)。使用 MAD1 序列，显微镜检查、分光光度法和流式细胞术确定肽的抗癌机制，而平行组合筛选定义了耐药细胞系和患者衍生的离体肿瘤中的化学治疗协同作用。

结果

SAR 调查显示两亲区域的空间隔离增加了 ACP 的效力，但以特异性为代价。选择 MAD1 作为前导序列，机制研究确定该肽在癌细胞的质膜和核膜内形成孔状超分子组装体，以通过裂解和凋亡机制增强死亡。这种多样化的活性使 MAD1 能够与化疗药物广泛协同，对耐药性卵巢癌细胞和患者来源的肿瘤球体表现出显着的组合功效。

结论

我们表明，癌症特异性 ACP 可以使用大自然的 AMP 工具箱作为模板进行合理设计。选择抗菌肽 MAD1，我们展示了该策略打开大量合成生物疗法的潜力，为抗药性肿瘤提供新的组合机会。