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Anon-catalytic,mild, and easy-to-handle protecting group switched 1,3-dipolar cycloaddition (1,3-DC) between bior mono-N-protected Dha and C,N-cyclic azomethine imines, which affordv arious quaternary amino acids with diverse scaffolds,i sd isclosed. Specifically,n ormal-electron-demand 1,3-DC reaction occurs between biN protected Dha and C,Ncyclic azomethine imines,w hile inverse-electron-demand 1,3-DC reaction occurs between mono-N-protected Dha and C,Ncyclic azomethine imines.A bove all, the reactions can be carried out between peptides with Dha residues at the position of interest and C,N-cyclic azomethine imines,both in homogeneous phase and on resins in SPPS.I tp rovides an ew toolkit for late-stage peptide modification, labeling,and peptide-drug conjugation. To shed light on the high regioselectivity of the reaction, DFT calculations were carried out, which were qualitatively consistent with the experimental observations.

The development of antimicrobial compounds is now regarded as an urgent problem. Antimicrobial peptides (AMPs) have great potential to become novel antimicrobial drugs. Feleucin-K3 is an α-helical cationic AMP isolated from the skin secretion of the Asian bombinid toad species Bombina orientalis and has antimicrobial activity. In our previous studies, amino acid scanning of Feleucin-K3 was performed to determine the key site affecting its activity. In this study, we investigated and synthesized a series of analogues that have either a natural or an unnatural hydrophobic amino acid substitution at the fourth amino acid residue of Feleucin-K3. Among these analogues, Feleucin-K59 (K59), which has an α-(4-pentenyl)-Ala substitution, was shown to have increased antimicrobial activity against both standard and drug-resistant strains of clinical common bacteria, improved stability, no hemolytic activity at antimicrobial concentrations, and no resistance. In addition, K59 has potent antibiofilm activity in vitro. More importantly, K59 showed better antimicrobial and antibiofilm activities against drug-resistant bacteria in in vivo experiments in mice than traditional antibiotics. In this preliminary study of the mechanism of action, we found that K59 could rapidly kill bacteria by a dual-action mechanism of disrupting the cell membrane and binding to intracellular DNA, thus making it difficult for bacteria to develop resistance.

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