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Review
. 2011 Jul;68(13):2255-66.
doi: 10.1007/s00018-011-0717-3. Epub 2011 May 20.

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Andrea Giuliani  1 , Andrea C Rinaldi
Affiliations
Review

Beyond natural antimicrobial peptides: multimeric peptides and other peptidomimetic approaches

Andrea Giuliani et al. Cell Mol Life Sci. 2011 Jul.

Abstract

Naturally occurring antimicrobial peptides (AMPs) present several drawbacks that strongly limit their development into therapeutically valuable antibiotics. These include susceptibility to protease degradation and high costs of manufacture. To overcome these problems, researchers have tried to develop mimics or peptidomimetics endowed with better properties, while retaining the basic features of membrane-active natural AMPs such as cationic charge and amphipathic design. Protein epitope mimetics, multimeric (dendrimeric) peptides, oligoacyllysines, ceragenins, synthetic lipidated peptides, peptoids and other foldamers are some of the routes explored so far. The synthetic approach has led to compounds that have already entered clinical evaluation for the treatment of specific conditions, such as Staphylococcus (MRSA) infections. Should these trials be successful, an important proof-of-concept would be established, showing that synthetic oligomers rather than naturally occurring molecules could bring peptide-based antibiotics to clinical practice and the drug market for local and systemic treatment of medical conditions associated with multi-drug resistant pathogens.

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Conflict of interest statement

One of the authors declares competing financial interests. Andrea Giuliani is an executive board member and minor shareholder of Spider Biotech S.r.l. (www.spiderbiotech.com), which is developing peptide-based anti-infectives.

Figures

Fig. 1
Fig. 1
Primary sequence and structure of the dendrimeric (tetrameric) antimicrobial peptide SB041. 5-Ava 5-amino valeric acid, pyrE pyroglutamic acid. All amino acids have l-configuration. The peptide is amidated at the C-terminus (5-Ava)
Fig. 2
Fig. 2
Structure of a β-hairpin PEM molecule. PEMs typically comprise a peptide loop linked to a β-hairpin-stabilizing template (e.g., the d-Pro-l-Pro dipeptide shown here)
Fig. 3
Fig. 3
a Acyl-lysyl oligomers (brackets define the building blocks); b chemical structure of ceragenin CSA-13
Fig. 4
Fig. 4
Representative SMAMP based on arylamide (a) and phenylene ethynylene oligomers (b)
Fig. 5
Fig. 5
Library of ROMP-based SMAMP polymers. Two synthetic platform were devised, one based on norbornene-imide derivatives (a), the other on norbornene-ester derivatives (b). The parent series is marked in red and underwent hydrophobic modification (green), hydrophilic or charge-related variations (blue), or counterion exchange (light green). One SMAMP was modified with guanidinium groups (grey). Reproduced from [37], with permission
Fig. 6
Fig. 6
Structure of an antimicrobial synthetic lipopeptide with the sequence C12-Orn-Orn-Trp-Trp-NH2
Fig. 7
Fig. 7
N-Substituted glycine monomers used for the construction of helical peptoids (ampetoids) in the laboratory of Annelise Barron [46]. aN-(2-carboxyethyl) glycine; bN-(4-aminobutyl) glycine; c (S)-N-(1-phenylethyl) glycine; d (S)-N-(1-naphthylethyl) glycine; e (S)-N-(1-methylbutyl) glycine; f (S)-N-(sec-butyl) glycine; g (R)-N-(1-phenylethyl) glycine; hN-(methylimidazole) glycine. From [61]
Fig. 8
Fig. 8
a Hypothesis explaining the activity of many host-defense peptides, involving the adoption of a globally amphiphilic helical conformation upon approach to a biomembrane surface; b alternative hypothesis, involving the adoption of a globally amphiphilic irregular conformation, which could explain the activity of α/β-peptides and random-sequence copolymers. Reproduced and modified from [54], with permission
Fig. 9
Fig. 9
Monomers used for the synthesis of random-sequence nylon-3 copolymers in [54]. Polymers were prepared from two types of β-lactams, some that led ultimately to cationic subunits—MM (monomethyl) or DM (dimethyl)—and others that provided lipophilic subunits—CP (cyclopentyl), CHx (cyclohexyl), CHp (cycloheptyl), CO (cyclooctyl). All β-lactams were used as racemic mixtures. Reproduced from [54], with permission
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