Synthetic Peptide Libraries Designed From a Minimal Alpha-Helical Domain of AS-48-Bacteriocin Homologs Exhibit Potent Antibacterial Activity

Rationally Designed Minimal Bioactive Domains of AS-48 Bacteriocin Homologs Possess Potent Antileishmanial Properties

“…In addition, five of these syn-safencin peptide variants with potent intracellular activity had amino acids replaced with lysine toward the N terminus, between positions 4 and 9. The replacement of amino acids with tryptophan toward either the N terminus or the C terminus has been shown previously to improve antimicrobial activity ( 50 ), consistent with our findings that these key amino acid positions are critical for activity.…”

“…Due to this previously confirmed parasiticidal activity, we hypothesized that AS-48-based minimal domain peptides can also exhibit antileishmanial properties. In this paper, we demonstrate the use of rationally designed minimal AS-48 bacteriocin homologs for antileishmanial drug candidate identification; 9 of the 480 peptides exhibited potent activity against Leishmania donovani intracellular amastigotes with IC 50 values of less than 4 μM, which is within the target product profile (TPP) established by the Drugs for Neglected Diseases Initiative (DNDi) ( 50 ).…”

“…Truncation of the linear form identified that the membrane-penetrating activity of enterocin AS-48 is attributed to a specific α-helical region on the circular peptide, which largely contains cationic residues ( 49 ). Previously, we utilized specific rational design techniques using AS-48 bacteriocin homologs to design a series of reductive peptide variants of AS-48 optimized for membrane-penetrating bioactivity, which subsequently demonstrated potent antibacterial activity ( 50 ). Other studies have shown that full-length enterocin AS-48 induced mitochondrial damage to Leishmania promastigotes and also exhibited 50% inhibitory concentration (IC 50 ) values against Leishmania pifanoi axenic amastigotes of 10.2 ± 1.2 μM ( 51 ).…”

A Seed-Endophytic Bacillus safensis Strain With Antimicrobial Activity Has Genes for Novel Bacteriocin-Like Antimicrobial Peptides

“…While we know of several circular bacteriocins have been reported in the literature, no natural linear variants of the AS-48 bacteriocin have been isolated from natural sources ( Xin et al, 2020 ). Previous work has shown that AS-48-like bacteriocins can still retain antimicrobial activity when reduced to a linear version ( Montalbán-López et al, 2008 ; Fields et al, 2018 ; Ross et al, 2020 ). The findings with Safencin demonstrated that only the cationic C-terminal residues 39–70 of the mature peptide were required for antimicrobial activity ( Fields et al, 2018 ).…”

Disrupting GPCR Complexes with Smart Drug-like Peptides

“…The first useful item in the toolbox is trimming off some N-terminal or C-terminal residues until a minimally active primary structure can be established (Figure 2A). This reductionistic approach is particularly efficacious in the case of TM peptides since, by removing (almost invariably hydrophobic) residues from the cognate TM sequence, water solubility is improved [70][71][72], while synthesis time and costs are considerably reduced. Another strategy to improve peptide solubility is PEGylation, i.e., attaching several polyethylene glycol (PEG) units to the peptide lead structure (Figure 2B).…”