Design, Synthesis, and Biological Evaluation of Lipidated Pentapeptide Derivatives Containing Unnatural Amino Acids.

INTRODUCTION/OBJECTIVE: The development of novel peptide-based therapeutics offers a promising strategy to overcome the limitations associated with conventional antibacterial drugs. This study aimed to design and synthesize a new series of lipidated pentapeptide derivatives containing unusual amino acids and to evaluate their antibacterial and antifungal potential. METHODS: A series of lipidated pentapeptides incorporating unconventional amino acids was designed and synthesized to enhance structural diversity, membrane interaction, amphiphilicity, and resistance to enzymatic degradation. Lipophilic moieties were introduced to improve peptide stability and biological performance. The synthesized compounds were characterized using standard analytical techniques and evaluated for their antibacterial and antifungal activities against selected Gram-positive and Gram-negative bacterial strains and pathogenic fungi. RESULTS: Several lipidated pentapeptide derivatives exhibited promising antibacterial activity against both Gram-positive and Gram-negative bacteria. In addition, notable antifungal activity was observed against pathogenic fungal strains. The results demonstrated that lipidation significantly enhanced the antimicrobial efficacy of the peptides. Among these peptide derivatives, compound 6a exhibited antibacterial activity against E. coli with MIC = 150 μg/mL, whereas compound 6b showed activity against S. aureus with MIC = 250 μg/mL. Compound 6c demonstrated the strongest antifungal activity against Candida albicans (MIC = 40 μg/mL), while compound 6e showed activity against Aspergillus niger (MIC = 80 μg/mL). DISCUSSION: The findings highlight peptide lipidation as an effective structural modification strategy to improve membrane interaction, bioactivity, and enzymatic stability of antimicrobial peptides. The incorporation of unusual amino acids further contributed to enhanced resistance against degradation, supporting their therapeutic potential. CONCLUSION: This study demonstrates that lipidated pentapeptide derivatives represent promising candidates for next-generation antimicrobial agents. Peptide lipidation emerges as a valuable approach for developing stable and potent peptide-based therapies to combat bacterial and fungal infections.