Synthesis of Fmoc-Triazine Amino Acids and Its Application in the Synthesis of Short Antibacterial Peptidomimetics.

Pethaiah Gunasekaran,Eun Kyoung Ryu,Jeong Kyu Bang,Eun Young Kim,Song Yub Shin,Jian Lee

doi:10.3390/ijms21103602

Abstract

To combat the escalating rise of antibacterial resistance, the development of antimicrobial peptides (AMPs) with a unique mode of action is considered an attractive strategy. However, proteolytic degradation of AMPs remains the greatest challenge in their transformation into therapeutics. Herein, we synthesized Fmoc-triazine amino acids that differ from each other by anchoring either cationic or hydrophobic residues. These unnatural amino acids were adopted for solid-phase peptide synthesis (SPPS) to synthesize a series of amphipathic antimicrobial peptidomimetics. From the antimicrobial screening, we found that the trimer, BJK-4 is the most potent short antimicrobial peptidomimetic without showing hemolytic activity and it displayed enhanced proteolytic stability. Moreover, the mechanism of action to kill bacteria was found to be an intracellular targeting.

Highlights

Antibiotics play vital roles in health care since the invention of penicillin
Synthesis of triazine based Fmoc amino acids and further construction of amphipathic peptidomimetics are feasible by controlling the substitution
Having synthesized the amphipathic peptidomimetics, we evaluated the antimicrobial activities of these peptidomimetics against a panel of both Gram-positive and Gram-negative bacterial strains, with the reference, melittin, which is a 26-aminoacid sequenced antimicrobial peptide obtained from venom of European honeybee, Apis mellifera [29,30]

Summary

Introduction

Antibiotics play vital roles in health care since the invention of penicillin. frequent and excessive misuse of antibiotics contributes to the escalating threat of antibiotic resistance [1,2]. A combination of a rapid increase of multidrug-resistant (MDR) pathogens and a noticeable scarcity in the development of a new class of antibiotics necessitate the discovery of new and alternative potent antimicrobial agents [5]. In this regard, antimicrobial peptides (AMPs) attract significant attention as a new generation antibiotics to combat the drug-resistant pathogens because they are widely present in species ranging from bacteria to mammals as a host defense system and exhibit potent antimicrobial activities [6]. Usage of AMPs with sequences that are similar to that of the human defense system, may cause an inevitable loss in the natural defense [10]

Methods

Results

Conclusion