Department of Chemistry and Biotechnology, Faculty of Science, Engineering and Technology, Swinburne University of Technology, PO Box 218, Hawthorn, VIC 3122, Australia.
Centre for Micro-Photonics, Faculty of Science, Engineering and Technology, Swinburne University of Technology, PO Box 218, Hawthorn, VIC 3122, Australia.
Int J Mol Sci. 2020 Nov 16;21(22):8624. doi: 10.3390/ijms21228624.
Antimicrobial peptides (AMPs) often exhibit wide-spectrum activities and are considered ideal candidates for effectively controlling persistent and multidrug-resistant wound infections. PuroA, a synthetic peptide based on the tryptophan (Trp)-rich domain of the wheat protein puroindoline A, displays strong antimicrobial activities. In this work, a number of peptides were designed based on PuroA, varying in physico-chemical parameters of length, number of Trp residues, net charge, hydrophobicity or amphipathicity, D-versus L-isomers of amino acids, cyclization or dimerization, and were tested for antimicrobial potency and salt and protease tolerance. Selected peptides were assessed for effects on biofilms of methicillin-resistant (MRSA) and selected mammalian cells. Peptide P1, with the highest amphipathicity, six Trp and a net charge of +7, showed strong antimicrobial activity and salt stability. Peptides W7, W8 and WW (seven to eight residues) were generally more active than PuroA and all diastereomers were protease-resistant. PuroA and certain variants significantly inhibited initial biomass attachment and eradicated preformed biofilms of MRSA. Further, P1 and dimeric PuroA were cytotoxic to HeLa cells. The work has led to peptides with biocidal effects on common human pathogens and/or anticancer potential, also offering great insights into the relationship between physico-chemical parameters and bioactivities, accelerating progress towards rational design of AMPs for therapeutics.
抗菌肽（AMPs）通常具有广谱活性，被认为是有效控制持续性和多药耐药性伤口感染的理想候选物。PuroA 是一种基于小麦蛋白 puroindoline A 的色氨酸（Trp）丰富结构域的合成肽，具有很强的抗菌活性。在这项工作中，基于 PuroA 设计了许多肽，它们在长度、Trp 残基数量、净电荷、疏水性或两亲性、氨基酸的 D-对 L-异构体、环化或二聚化等理化参数上有所不同，并对其抗菌效力以及盐和蛋白酶耐受性进行了测试。选择了一些肽来评估它们对耐甲氧西林金黄色葡萄球菌（MRSA）和选定的哺乳动物细胞生物膜的影响。具有最高两亲性、六个 Trp 和净电荷为+7 的肽 P1 表现出很强的抗菌活性和盐稳定性。肽 W7、W8 和 WW（七到八个残基）通常比 PuroA 更具活性，所有非对映异构体都具有蛋白酶抗性。PuroA 和某些变体显著抑制了 MRSA 初始生物量的附着并根除了已形成的生物膜。此外，P1 和二聚体 PuroA 对 HeLa 细胞具有细胞毒性。这项工作产生了对常见人类病原体具有杀菌作用的肽和/或具有抗癌潜力的肽，还深入了解了理化参数与生物活性之间的关系，为合理设计治疗性 AMP 提供了帮助。
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