Peptide Stapling Applied to Antimicrobial Peptides

Abstract

Antimicrobial peptides (AMPs) are considered a promising therapeutic approach against multi-drug resistant microorganisms. Besides their advantages, there are limitations to be overcome so that these molecules can become market competitive. One of the biggest limitations is proteolytic susceptibility, which could be overcome by structural modifications such as cyclization, especially for helix-constraining strategies. Over the years, many helix stabilization techniques have arisen, such as lactam-bridging, triazole-based, N-alkylation and all-hydrocarbon stapling. All-hydrocarbon stapling takes advantage of modified amino acid residues and olefinic cross-linking to constrain peptide helices. Despite being a well-established strategy and presenting efficient stability results, there are different limitations especially related to toxicity. In this review, recent studies on stapled AMPs for antimicrobial usage are explored with the aim of understanding the future of these molecules as putative antimicrobial agents.

Keywords: all-hydrocarbon stapling; antimicrobial peptides; cyclization; stapling.

Figure 1

Cyclization and stapling strategies. Cyclization strategies (A) varying the linked positions in the peptide structure and stapling (B–E), which is a type of side chain-to-side chain cyclization, in which the most common positions are i, i + 4 (B) and i, i + 7 (C) for a single staple and possible positions for double stapling (D) and stitching (E).

Figure 2

Classification of AMPs deposited on the Data Repository of Antimicrobial Peptides (DRAMP) describing (A) type of AMP, (B) most common positions for stapled AMPs and (C) stapling strategy applied.

Figure 3

Cross-linking mediated by ruthenium-catalyzed ring-closing metathesis (RCM) between non-natural amino acids presenting S (A) and/or R (B) stereochemistry forming the staple at the desirable position within the α-helix structure.