Malaria is a serious threat to human health and additional classes of antimalarial drugs are greatly needed. The human defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity but also undesirable chemokine properties. We engineered a peptide containing the isolated PF4 antiplasmodial domain, which through cyclization, retained the critical structure of the parent protein. The peptide, cPF4PD, killed cultured blood-stagePlasmodium falciparumwith low micromolar potency by specific disruption of the parasite digestive vacuole. Its mechanism of action involved selective penetration and accumulation inside the intraerythrocytic parasite without damaging the host cell or parasite membranes; it did not accumulate in uninfected cells. This selective activity was accounted for by observations of the peptide's specific binding and penetration of membranes with exposed negatively charged phospholipid headgroups. Our findings highlight the tremendous potential of the cPF4PD scaffold for developing antimalarial peptide drugs with a distinct and selective mechanism of action.

中文翻译：

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人血小板因子4改造的防御肽通过选择性膜破坏杀死疟原虫。

疟疾是对人类健康的严重威胁，因此非常需要其他种类的抗疟药。人类防御蛋白血小板因子4（PF4）具有固有的抗血浆活性，但也具有不希望的趋化因子特性。我们设计了一种包含分离的PF4抗血浆结构域的肽，该肽通过环化作用保留了亲本蛋白质的关键结构。通过特异性破坏寄生虫消化液，cPF4PD肽杀死了具有低微摩尔效价的恶性疟原虫。它的作用机制包括在红细胞内寄生虫内选择性渗透和积累，而不会破坏宿主细胞或寄生虫膜。它没有在未感染的细胞中积累。这种选择性活性是通过观察肽的“肽”来解释的。具有暴露的带负电的磷脂头基的膜的特异性结合和渗透。我们的发现凸显了cPF4PD支架在开发具有独特和选择性作用机制的抗疟肽药物方面的巨大潜力。