Rational Design of Helix‐Stabilized Antimicrobial Peptide Foldamers Containing α, α‐Disubstituted Amino Acids or Side‐Chain Stapling. Issue 12 (28th December 2020)

• Record Type: Journal Article
• Authors: Hirano, Motoharu; Saito, Chihiro; Goto, Chihiro; Yokoo, Hidetomo; Kawano, Ryuji; Misawa, Takashi; Demizu, Yosuke
• Is Part Of: ChemPlusChem. Volume 85:Issue 12(2020)
• Page Start: 2731
• Page End: 2736
• Publication Date: 2020-12-28
• Subjects: amphipathic peptides -- antimicrobial activity -- foldamers -- helical structures -- hemolysis; Chemistry -- Periodicals; 540.5
• DOI: 10.1002/cplu.202000749
• Languages: English
• ISSNs: 2192-6506

Abstract

Abstract: 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. Abstract : Antimicrobially active peptide : Rationally‐designed antimicrobial peptide (AMP) foldamers containing Leu, Lys, and non‐proteinogenic amino acid residues were synthesized. Those AMPs containing α, α‐disubstituted α‐amino acids (Aib, Ac6 c) or a side‐chain stapling were folded into stable helical structures. In particular, the peptide which contained Aib residues showed potent activity against both Gram‐positive and Gram‐negative bacteria, as well as low hemolytic activity.Demizu, Misawa et al. @YCU_koho report rational design of helix‐stabilized antimicrobial peptide foldamers containing α, α‐disubstituted amino acids or side‐chain stapling #foldamers