Uncoupling the Folding-Function Paradigm of Lytic Peptides to Deliver Impermeable Inhibitors of Intracellular Protein–Protein Interactions,Journal of the American Chemical Society

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Uncoupling the Folding-Function Paradigm of Lytic Peptides to Deliver Impermeable Inhibitors of Intracellular Protein–Protein Interactions
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2020-11-11 , DOI: 10.1021/jacs.0c07921
Stephen E Miller ₁ , Kohei Tsuji ₁ , Rachel P M Abrams ₂ , Terrence R Burke ₁ , Joel P Schneider ₁

Affiliation

Here, we describe the use of peptide backbone N-methylation as a new strategy to transform membrane-lytic peptides (MLPs) into cytocompatible intracellular delivery vehicles. The ability of lytic peptides to engage with cell membranes has been exploited for drug delivery to carry impermeable cargo into cells, but their inherent toxicity results in narrow therapeutic windows that limit their clinical translation. For most linear MLPs, a prerequisite for membrane activity is their folding at cell surfaces. Modification of their backbone with N-methyl amides inhibits folding, which directly correlates to a reduction in lytic potential but only minimally affects cell entry. We synthesized a library of N-methylated peptides derived from MLPs and conducted structure-activity studies that demonstrated the broad utility of this approach across different secondary structures, including both β-sheet and helix-forming peptides. Our strategy is highlighted by the delivery of a notoriously difficult class of protein-protein interaction inhibitors that displayed on-target activity within cells.

中文翻译：

解偶联裂解肽的折叠功能范式以提供细胞内蛋白质-蛋白质相互作用的不可渗透抑制剂

在这里，我们描述了使用肽主链 N-甲基化作为将膜溶解肽（MLP）转化为细胞相容性细胞内递送载体的新策略。裂解肽与细胞膜结合的能力已被用于药物递送，将不可渗透的货物携带到细胞中，但其固有的毒性导致治疗窗口狭窄，限制了其临床转化。对于大多数线性 MLP，膜活性的先决条件是它们在细胞表面的折叠。用 N-甲基酰胺对其主链进行修饰会抑制折叠，这与裂解电位的降低直接相关，但对细胞进入的影响很小。我们合成了源自 MLP 的 N-甲基化肽库，并进行了结构活性研究，证明了该方法在不同二级结构（包括 β-折叠肽和螺旋形成肽）中的广泛实用性。我们的策略的重点是提供一类众所周知的困难的蛋白质-蛋白质相互作用抑制剂，这些抑制剂在细胞内显示出靶向活性。

更新日期：2020-11-11

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