Development of Therapeutic Gramicidin S Analogues Bearing Plastic β, γ‐Diamino Acids. (20th May 2020)

• Record Type: Journal Article
• Authors: Guan, Qinkun; Chen, Kaisen; Chen, Qiang; Hu, Jianguo; Cheng, Keguang; Hu, Chengfei; Zhu, Jibao; Jin, Yi; Miclet, Emeric; Alezra, Valérie; Wan, Yang
• Is Part Of: ChemMedChem. Volume 15:Number 12(2020)
• Page Start: 1089
• Page End: 1100
• Publication Date: 2020-05-20
• Subjects: antimicrobial peptide -- beta, gamma-diamino acids -- gramicidin S -- hemolysis -- membrane disruption; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202000097
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: Gramicidin S (GS), one of the most widely investigated antimicrobial peptides (AMPs), is known for its robust antimicrobial activity. However, it is restricted to topical application due to undesired hemolytic activity. With the aim of obtaining nontoxic GS analogues, we describe herein a molecular approach in which the native GS β‐turn region is replaced by synthetic β, γ‐diamino acids (β, γ‐DiAAs). Four β, γ‐DiAA diastereomers were employed to mimic the β‐turn structure to afford GS analogues GS3 –6, which exhibit diminished hemolytic activity. A comparative structural study demonstrates that the (β R, γ S )‐DiAA is the most‐stable β‐turn mimic. To further improve the therapeutic index (e. g., high antibacterial activity and low hemolytic activity) and to extend the molecular diversity, GS5 and GS6 were used as structural scaffolds to introduce additional hydrophobic or hydrophilic groups. We show that GS6K, GS6F and GS display comparable antibacterial activity, and GS6K and GS6F have significantly decreased toxicity. Moreover, antibacterial mechanism studies suggest that GS6K kills bacteria mainly through the disruption of the membrane. Abstract : The native motif D Phe‐Pro of the antimicrobial peptide gramicidin S (GS) was monosubstituted with a series of synthetic (β, γ)‐diamino acids to afford nontoxic GS analogues. The analogue GS6K included with (β R, γ S )‐diamino acid has a sheet‐like conformation comparable to that of GS. GS6K displays both potent bactericidal activity and diminished hemolytic effect. It appears to kill bacteria mainly through membrane disruption.