The global increase in antimicrobial drug resistance has dramatically reduced the effectiveness of traditional antibiotics. Structurally diverse antibiotics are urgently needed to combat multiple-resistant bacterial infections. As part of innate immunity, antimicrobial peptides have been recognized as the most promising candidates because they comprise diverse sequences and mechanisms of action and have a relatively low induction rate of resistance. However, because of their low chemical stability, susceptibility to proteases, and high hemolytic effect, their usage is subject to many restrictions. Chemical modifications such as D-amino acid substitution, cyclization, and unnatural amino acid modification have been used to improve the stability of antimicrobial peptides for decades. Among them, a side-chain covalent bridge modification, the so-called stapled peptide, has attracted much attention. The stapled side-chain bridge stabilizes the secondary structure, induces protease resistance, and increases cell penetration and biological activity. Recent progress in computer-aided drug design and artificial intelligence methods has also been used in the design of stapled antimicrobial peptides and has led to the successful discovery of many prospective peptides. This article reviews the possible structure-activity relationships of stapled antimicrobial peptides, the physicochemical properties that influence their activity (such as net charge, hydrophobicity, helicity, and dipole moment), and computer-aided methods of stapled peptide design. Antimicrobial peptides under clinical trial: Pexiganan (NCT01594762, 2012-05-07). Omiganan (NCT02576847, 2015-10-13).
Keywords: Alpha helix; Antimicrobial activity; Antimicrobial peptide; Computer design; Hemolytic activity; Stapled antimicrobial peptide.
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Austria, part of Springer Nature.