D-N3R2(Lanzhou University)

The antimicrobial activity and toxicity of β-hairpin antimicrobial peptides (AMPs) primarily depend on their intramolecular β-sheet structure, which is crucially affected by the β-turn sequence. To determine whether the tryptophan or arginine motifs in the β-turn of β-hairpin AMPs exhibit greater therapeutic efficacy, a library of β-hairpin AMPs was designed based on the simplified template: (WK)_nX_m(KW)_n-NH₂ (X = Trp or Arg; n = 1, 2, 3; m = 1, 2, 3). The results indicate that AMPs containing arginine motifs within the β-turn sequence exhibit superior antibacterial activity and enhanced therapeutic efficacy. Notably, peptide N3R2 with "-RR-" as the symmetry center displayed potent antimicrobial activity and low toxicity. The enantiomer of N3R2, named D-N3R2, was synthesized to enhance proteolytic stability. D-N3R2 exhibited even more potent antimicrobial activity than N3R2. Furthermore, we comprehensively investigated the efficacy and toxicity in vitro and in vivo, stability, SAR, and mechanism of action.