Multivalent Antimicrobial Peptides as Therapeutics: Design Principles and Structural Diversities

Abstract

This review highlights the design principles, progress and advantages attributed to the structural diversity associated with both natural and synthetic multivalent antimicrobial peptides (AMPs). Natural homo- or hetero-dimers of AMPs linked by intermolecular disulfide bonds existed in the animal kingdom, but the multivalency strategy has been adopted to create synthetic branched or polymeric AMPs that do not exist in nature. The multivalent strategy for the design of multivalent AMPs provides advantages to overcome the challenges faced in clinical applications of AMPs, such as: stability, efficiency, toxicity, maintenance of activity in high salt concentrations and under physiological conditions, and importantly overcoming bacterial resistance which is currently a leading health problem in the world. The multivalency strategy is valuable for moving multivalent AMPs toward clinical applications.

Progressive Structuring of a Branched Antimicrobial Peptide on the Path to the Inner Membrane Target

“…In our own efforts of designing AMPs, we found that covalent linkage of monomeric AMPs contributed to a significant increase of antimicrobial activities (7,29). Higher covalent oligomerization generally tends to increase affinities to lipid surfaces (11).…”

“…More than 1000 different antimicrobial peptides have been documented with activity against viruses, bacteria, and fungi, prompting interest in using the structural principles of small cationic, amphiphilic molecules for improving and fine tuning target specificity and efficacy (3)(4)(5)(6). Non-natural multivalent AMPs have been designed by conjugating copies of a peptide monomer to scaffold molecules via naturally occurring intermolecular disulfide bridges or unnatural scaffold linkers (7). Branched peptides have been shown to have considerable advantages over their monomeric forms, such as improved antimicrobial activity (8), maintaining high efficacy under physiological (high salt) conditions (9,10), enhanced bacterial surface binding affinity (11), decreased susceptibility to proteolytic degradation (12,13), and low cytotoxicity (14,15).…”

Interaction of blood components with cathelicidins and their modified versions

“…cAMPs are attracted to bacterial surfaces by electrostatic interaction, but could directly interact with host cells and lyse them. Sometimes the toxicity associated with cAMPs is related to the inherent hydrophobicity combined with high dose to compensate for their relatively short half-life due to the rapid protease digestion [10][11], or peptide aggregation [12]. Several structure-activity relation studies with AMPs suggest a direct correlation between peptide hydrophobicity and hemolytic activity [13][14][15].…”

Effects of Dimerization on the Structure and Biological Activity of Antimicrobial Peptide Ctx-Ha

“…Cationic antimicrobial peptides (cAMPs) appear to be an interesting alternative because they are not hindered by resistance mechanisms, which are placing conventional antibiotics in jeopardy (25). cAMPs are part of the innate defense systems of several organisms, including animals, plants, insects, and microorganisms, and exhibit a broad spectrum of antimicrobial activity against bacteria, fungi, and viruses (30).…”