Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa, 210-9501, Japan.
Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa, 230-0045, Japan.
Chempluschem. 2020 Dec;85(12):2731-2736. doi: 10.1002/cplu.202000749.
Antimicrobial peptides (AMPs) are expected to be good candidate molecules for novel antimicrobial therapies. Most AMPs exert their antimicrobial activity through disruption of microbial membranes due to their amphipathic properties. Recently, the helical peptide 'Stripe' was reported by our group, a rationally designed amphipathic AMP focused on distribution of natural cationic and hydrophobic amino acid residues. In this study, a set of Stripe-based AMP foldamers was designed, synthesized and investigated that contain α,α-disubstituted amino acids or side-chain stapling to stabilize their helical structures. Our results showed that a peptide containing 2-aminoisobutyric acid (Aib) residues exhibited potent antimicrobial activity against both Gram-positive S.aureus (MIC value: 3.125 μM) and Gram-negative bacteria (including a multidrug-resistant strain, MDRP, MIC value: 1.56 μM), without significant hemolytic activity (>100 μM). Electrophysiological measurements revealed that this peptide formed stable pores in a 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE)/1,2-dioleoyl-sn-glycero-3-phosphoglycerol (DOPG) bilayer but not in a dioleoylphosphocholine (DOPC) bilayer. The introduction of Aib residues into Stripe could be a promising way to increase the antimicrobial activity of AMP foldamers, and the peptide could represent a promising novel therapeutic candidate to treat multidrug-resistant bacterial infection.
抗菌肽（AMPs）有望成为新型抗菌疗法的候选分子。由于具有两亲性，大多数 AMP 通过破坏微生物膜来发挥其抗菌活性。最近，我们小组报道了一种名为“Stripe”的螺旋肽，这是一种经过合理设计的两亲性 AMP，专注于分布天然阳离子和疏水性氨基酸残基。在这项研究中，设计、合成并研究了一组基于 Stripe 的 AMP 类折叠物，其中包含α，α-二取代氨基酸或侧链订书钉以稳定其螺旋结构。我们的结果表明，含有 2-氨基异丁酸（Aib）残基的肽对革兰氏阳性菌 S.aureus（MIC 值：3.125 μM）和革兰氏阴性菌（包括耐多药菌株，MDRP，MIC 值：1.56 μM）均表现出很强的抗菌活性，而溶血活性没有明显变化（>100 μM）。电生理测量表明，该肽在 1,2-二油酰基-sn-甘油-3-磷酸乙醇胺（DOPE）/1,2-二油酰基-sn-甘油-3-磷酸甘油（DOPG）双层中形成稳定的孔，但不在二油酰基磷酸胆碱（DOPC）双层中形成。在 Stripe 中引入 Aib 残基可能是提高 AMP 类折叠物抗菌活性的一种有前途的方法，该肽可能代表一种有前途的新型治疗候选药物，可用于治疗耐多药细菌感染。
