De novo Design of Selective Membrane-Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface.,Angewandte Chemie International Edition

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De novo Design of Selective Membrane-Active Peptides by Enzymatic Control of Their Conformational Bias on the Cell Surface.
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2019-07-26 , DOI: 10.1002/anie.201902470
Junfeng Shi ₁ , Joel P Schneider ₁

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Selectively targeting the membrane-perturbing potential of peptides towards a distinct cellular phenotype allows one to target distinct populations of cells. We report the de novo design of a new class of peptide whose ability to perturb cellular membranes is coupled to an enzyme-mediated shift in the folding potential of the peptide into its bioactive conformation. Cells rich in negatively charged surface components that also highly express alkaline phosphatase, for example many cancers, are susceptible to the action of the peptide. The unfolded, inactive peptide is dephosphorylated, shifting its conformational bias towards cell-surface-induced folding to form a facially amphiphilic membrane-active conformer. The fate of the peptide can be further tuned by peptide concentration to affect either lytic or cell-penetrating properties, which are useful for selective drug delivery. This is a new design strategy to afford peptides that are selective in their membrane-perturbing activity.

中文翻译：

通过酶控制细胞表面构象偏差从头设计选择性膜活性肽。

选择性地将肽的膜扰动潜力靶向不同的细胞表型，使得人们能够靶向不同的细胞群。我们报告了一种新型肽的从头设计，其干扰细胞膜的能力与酶介导的肽折叠潜力转变为其生物活性构象相结合。富含带负电表面成分且高度表达碱性磷酸酶的细胞（例如许多癌症）对肽的作用敏感。未折叠的无活性肽被去磷酸化，将其构象偏向转向细胞表面诱导的折叠，形成表面两亲性膜活性构象异构体。肽的命运可以通过肽浓度进一步调节，以影响溶解或细胞穿透特性，这对于选择性药物递送非常有用。这是一种新的设计策略，可提供具有选择性膜扰动活性的肽。

更新日期：2019-07-26

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