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.

Fig. 1

Schematic representation of dendrimeric/branched and polymeric multivalent peptides (a). The dendrimeric/branched core or scaffold molecules can be Lys or other molecules. One lys for divalent AMPs, three Lys for tetravalent AMPs and seven Lys for octavalent AMPs; (a-c) The core or scaffold may contain 2, 3, 4 or 8 connecting units that can be used to create divalent, trivalent, tetravalent and octavalent AMPs (a–c). d The peptide can be covalently linked to a polymerizable monomer or poymeric unit to produce peptide-polymer conjugates

Fig. 2

Relationship between therapeutic index with increasing number of repeats for linear and branched peptides. Note that the therapeutic index increases several fold for branched peptide s compared to linear peptides. Data taken from Tam et al. (2002)

Fig. 3

Structure of tetramer (RW)_4D. Redrawed structure from Liu et al. (2007)

Fig. 4

Effect of alanine substitution on antimicrobial properties of the tetrabranched peptide, M6. Each vertical bar represents the result of antimicrobial activity on single alanine substitution in the original sequence, which is shown on top. Note that alanine replacement of all hydrophobic residues lead to considerable decrease in antimicrobial activity whereas replacing charge residues with alanine decreased moderately (except K2). Data taken from Pini et al. (2005)

Fig. 5

The chemical structures of alkyne-functionalized 3,5-di-(2-aminoethoxy) benzoic acid-based dentritic core molecules (compounds 1-3 for divalent, tetravalent and octavalent maganin 2, respectively) which provide alkyne group for the Cu(I)-catalyzed alkyne-azide cycloaddition (named “click chemistry”) and the linkage spacer (a 1,4-disubstitued 1,2,3-triazole-linking spacer, structure 4), which was formed between maganin 2 and dendritic core molecules by click chemistry. Redrawed structure from Arnusch et al. (2007)

Fig. 6

The structures of polymeric form of vancomycin. Redrawed structure from Li and Xu (2005)

Fig. 7

Structure of polymeric AMPs based on 4-residue peptides (RWRW and RRWW) and a polymaleic anhydrde (PMA) chain. Redrawed structure from Liu et al. (2006)