For these reasons, we believe the all-hydrocarbon peptide stapling strategy could be an effective strategy for B1-Leu peptide optimization.

Increased helicity, hydrophobicity, and penetrative ability are key factors in AMPs’ biological activity ( Dinh et al., 2015 Luong et al., 2017 Migoń et al., 2018 Mourtada et al., 2019). The aliphatic side chain can also improve the hydrophobicity of peptides, to an extent. It can provide more rigid secondary structure and lock the desired spiral conformation, resulting in an increased protease stability, improved cell penetration, and higher target binding affinity ( Bird et al., 2010 Wang and Chou, 2015 Wang et al., 2015). The all-hydrocarbon peptide stapling strategy developed by Verdine and coworkers, which is realized through ring-closing metathesis between olefin-bearing amino acids, has become one of the most recognized methods of peptidomimetic development ( Schafmeister et al., 2000). Structure modification strategies should be used to improve their physical and chemical properties. They do not readily maintain stable secondary structures and are susceptible to proteolytic degradation ( Marr et al., 2006). However, linear peptides may not be the best choice for novel drug development due to their poor pharmacokinetic properties. For this reason, B1-Leu peptide is now considered a potential candidate for cancer therapy. They deduced that B1-L peptide could disrupt the cell membrane and enter the cytoplasm, then act on the mitochondria to stimulate the release of cytochrome C. (2015) showed that B1-Leu peptide exerts more pronounced anticancer activity than B1 peptide against drug-resistant cell lines, such as MCF-7/ADM and K562/ADM. Besides, they also have excellent antitumor activity with complex mechanisms and show obvious advantages, such as a greater specificity and avoiding drug resistance, over traditional antitumor drugs ( Hoskin and Ramamoorthy, 2008 Housman et al., 2014).ī1 (VKRFKKFFRKLKKSV-NH 2) and B1-Leu peptide (B1-L, VKRFKKFFRKLKKLV-NH 2) are both structural optimization peptides derived from lysine- and phenylalanine-rich AMP cathelicidin-BF found in the venom of the snake Bungarus fasciatus ( Chen et al., 2011 Deng et al., 2015). Research has shown that AMPs have broad-spectrum antimicrobial effects, and their sterilization mechanism makes it difficult for pathogens to produce drug-resistant mutations ( Travkova et al., 2017 Savini et al., 2020). (1989) isolated cecropin from Hyalophora cecropia in 1975, more than a thousand species of AMPs derived from viruses, bacteria, plants, insects, mollusks, crustaceans, amphibians, fish, birds, and mammals have been confirmed and studied ( Waghu et al., 2016). Antimicrobial peptides (AMPs), a class of organic endogenous protective peptides, play important roles in both biological innate immunity and acquired immunity ( Tornesello et al., 2020 Hancock et al., 2021 Li et al., 2021).

Stapled secondary