Design of potent and salt-insensitive antimicrobial branched peptides

• Main Authors: To, Janet, Zhang, Xiaohong, Tam, James P.
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2023
• Subjects: Science::Biological sciences; Peptide Dendrimers; Antimicrobial Peptides; Polymeric Scaffolds; Isolysine Scaffold; Lysine Reverse Turns; Branched Peptides
• Online Access: https://hdl.handle.net/10356/170612
• Institution: Nanyang Technological University

Dendrimeric and branched peptides are polypeptides formed by diverse types of scaffolds to give them different forms. Previously, we reported a cascade-type, Lys-scaffolded antimicrobial peptide dendrimer D4R tethered with four RLYR tetrapeptides. Antimicrobial D4R is broad-spectrum, salt insensitive, and as potent as the natural-occurring tachyplesins, displaying minimum inhibitory concentrations (MIC) < 1 M. However, the relationships between scaffolds and antimicrobial potency remain undefined. Here, we report the design of four novel types of peptide antimicrobials whose scaffolded backbones are lysine (Lys), iso-Lys, ornithine (Orn), or iso-Orn tethered with RLYR on their - or sidechain-amines to give "-, -, and their -branched peptides. When assayed against ten microorganisms, the Lys-scaffolded - and "-branched peptides are broadly active, salt insensitive, and as potent as D4R and tachyplesins, whereas the corresponding Orn-scaffolded -and -branched peptides are salt sensitive and much less potent, displaying MICs ranging from 1 to >500 M. Structure-activity relationship studies suggested that Lys-scaffolds, but not Ornscaffolds, can support a reverse turn to organize RLYR tetrapeptides as parallel -strands to form an amphipathic structure with Leu-Tyr as a hydrophobic core. Together, these results provide a structural approach for designing potent and salt-insensitive dendrimeric or branched peptide antimicrobials.