One powerful application of cell penetrating peptides is the delivery into cells of molecules that function as specific competitors or inhibitors of protein-protein interactions. Ablating defined protein-protein interactions is a refined way to explore their contribution to a particular cellular phenotype in a given disease context. Cell-penetrating peptides can be synthetically constrained through various chemical modifications that stabilize a given structural fold with the potential to improve competitive binding to specific targets. Theileria-transformed leukocytes display high PKA activity, but PKA is an enzyme that plays key roles in multiple cellular processes; consequently genetic ablation of kinase activity gives rise to a myriad of confounding phenotypes. By contrast, ablation of a specific kinase-substrate interaction has the potential to give more refined information and we illustrate this here by describing how surgically ablating PKA interactions with BAD gives precise information on the type of glycolysis performed by Theileria-transformed leukocytes. In addition, we provide two other examples of how ablating specific protein-protein interactions in Theileria-infected leukocytes leads to precise phenotypes and argue that constrained penetrating peptides have great therapeutic potential to combat infectious diseases in general.

细胞穿透肽的一项强大应用是将充当蛋白质-蛋白质相互作用的特异性竞争者或抑制剂的分子传递到细胞中。消除定义的蛋白质-蛋白质相互作用是探索在给定疾病背景下它们对特定细胞表型的贡献的一种改良方法。可以通过各种化学修饰来合成限制细胞穿透的肽，这些化学修饰可以稳定给定的结构折叠，并具有改善与特定靶标的竞争结合的潜力。泰勒里亚转化的白细胞显示出高的PKA活性，但是PKA是一种在多种细胞过程中起关键作用的酶。因此，激酶活性的遗传消融产生了许多混杂的表型。相比之下，特定激酶-底物相互作用的消融有潜力提供更精细的信息，我们在这里通过描述如何通过手术消融PKA与BAD相互作用来给出有关由Theileria转化的白细胞进行的糖酵解类型的精确信息来说明这一点。此外，我们提供了两个其他示例来说明如何在Theileria中消除特定的蛋白质-蛋白质相互作用被感染的白细胞导致精确的表型，并认为受约束的穿透肽通常具有抵抗传染病的巨大治疗潜力。