Arginine N-glycosylation of melittin enhances its bacteriostatic activity and antiproliferative therapeutic index

Abstract

Melittin is a natural antimicrobial peptide isolated from bee venom, the non-specific cytotoxicity and hemolytic activity severely limit its clinical application. Glycosylation of protein is very common in physiological and biochemical processes, which can modulate the interaction of protein with its target. In this study, eight glycosyls were used to modify the arginine of melittin at site 22 and/or 24, single and double arginine N-glycosylated peptides were designed and synthesized. Among the acquired 24 glycopeptides, MLT-1c, MLT-3c, MLT-1f, MLT-3f, MLT-1g, MLT-3h were found to possess higher helicity, while MLT-3c, MLT-3f and MLT-3h obtained dramatically reduced hemolytic activity, especially MLT-3c whose HC50 value is 199.3 μM. MLT-1a, MLT-3a and MLT-2c got improved inhibition activity on Puzza streptococcus, the MIC were 4 μg/mL. MLT-1e and MLT-2g have strongest tolerance against trypsase, and MLT-3c has the highest therapeutic index. In general, rhamnosyl modified melittin MLT-3c could be a potent agent in antibacterial and antitumor therapy with high stability and low hemolytic side effect.