PDF(Pubmed)
Abstract：
The control of malaria, a disease caused by Plasmodium parasites that kills over half a million people every year, is threatened by the continual emergence and spread of drug resistance. Therefore, new molecules with different mechanisms of action are needed in the antimalarial drug development pipeline. Peptides developed from host defense molecules are gaining traction as anti-infectives due to theood of inducing drug resistance. Human platelet factor 4 (PF4) has intrinsic activity against P. falciparum, and a macrocyclic helix-loop-helix peptide derived from its active domain recapitulates this activity. In this study, we used a stepwise approach to optimize first-generation PF4-derived internalization peptides (PDIPs) by producing analogues with substitutions to charged and hydrophobic amino acid residues or with modifications to terminal residues including backbone cyclization. We evaluated the in vitro activity of PDIP analogues against P. falciparum compared to their overall helical structure, resistance to breakdown by serum proteases, selective binding to negatively charged membranes, and hemolytic activity. Next, we combined antiplasmodial potency-enhancing substitutions that retained favorable membrane and cell-selective properties onto the most stable scaffold to produce a backbone cyclic PDIP analogue with four-fold improved activity against P. falciparum compared to first-generation peptides. These studies demonstrate the ability to modify PDIP to select for and combine desirable properties and further validate the suitability of this unique peptide scaffold for developing a new molecule class that is distinct from existing antimalarial drugs.
摘要：
控制疟疾，一种由疟原虫寄生虫引起的疾病，每年杀死50多万人，受到耐药性的持续出现和传播的威胁。因此,抗疟药物开发管道需要具有不同作用机制的新分子。由宿主防御分子开发的肽由于具有诱导耐药性的作用而作为抗感染剂获得了吸引力。人血小板因子4（PF4）具有针对恶性疟原虫的内在活性，和来自其活性结构域的大环螺旋-环-螺旋肽概括了这种活性。在这项研究中,我们使用逐步方法优化第一代PF4衍生的内化肽(PDIPs),方法是产生对带电和疏水性氨基酸残基进行取代或对末端残基进行修饰(包括主链环化)的类似物.我们评估了PDIP类似物对恶性疟原虫的体外活性，与它们的整体螺旋结构相比，对血清蛋白酶分解的抗性，与带负电荷的膜选择性结合，和溶血活性。接下来,我们将保留有利的膜和细胞选择性的抗疟原虫效能增强取代结合到最稳定的支架上,以产生与第一代肽相比具有4倍改善的抗恶性疟原虫活性的骨架环状PDIP类似物.这些研究证明了修饰PDIP以选择和组合所需特性的能力，并进一步验证了这种独特的肽支架对于开发不同于现有抗疟药物的新分子类别的适用性。
