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.

Antimicrobial Peptides towards Clinical Application—A Long History to Be Concluded

“…AMPs are small bioactive proteins generally composed of 10-50 amino acids with a molecular weight of less than 10 KDa. Most AMPs are positively charged (2-13 net positive charges), derived primarily from lysine and arginine (a few may be histidine) in the sequence forming a specific cationic domain [17,18]. A few AMPs are negatively charged: examples are daptomycin and an antimicrobial neuroendocrine peptide called chrombacin, the latter bearing 12 net negative charges [19].…”