Modification and Targeted Design of N-Terminal Truncates Derived from Brevinin with Improved Therapeutic Efficacy

Abstract

Antimicrobial peptides (AMPs) are a class of molecules that play an essential role in innate immune regulation. The Brevinin-1 family are AMPs that show strong pharmacological and antimicrobial potential. A novel peptide, B1A, was designed based on the primary structure of brevinin-1PLb and brevinin-1PLc. Subsequently, a synthesised replicate was subjected to a series of bioassays and was found to display antimicrobial activity. However, it also displayed high levels of haemolysis in a horse red blood cell haemolytic assay, suggesting potential toxicity. Therefore, we rationally designed a number of B1A analogues with aim of retaining antimicrobial activity, lowering toxicity, and to explore the structure–activity relationship of its N-terminus. B1A and its analogues still retained the “Rana Box” and the FLP-motif, which is a feature of this subfamily. However, the introduction of Lys and Trp residues into the peptide sequences revealed that antimicrobial activity of these analogues remained unchanged once the hydrophobicity and the charge reached the threshold. Hence, the idea that the hydrophobicity saturation in different situations is related to antimicrobial activity can be understood via the structure–activity relationship. Meanwhile, it could also be the starting point for the generation of peptides with specific antimicrobial activity.

Bioevaluation and Targeted Modification of Temporin-FL From the Skin Secretion of Dark-Spotted Frog (Pelophylax nigromaculatus)

“…The helical wheel plots and prediction of the 3D secondary structure indicated that the three peptides have different hydrophobic faces and helical patterns. The small temporins are inactive against most bacterial strains ( Simmaco et al, 1996 ), however, truncation of amino acids is widely applied for adjusting peptide physicochemical properties, including membrane affinity ( Feng et al, 2020 ; He et al, 2020 ; Zhu et al, 2020 ). According to previous studies, modification of temporins is always performed via amino acids alteration or terminal sequence addition ( Mangoni et al, 2011 ; Bezzerri et al, 2014 ; Xie et al, 2019 ), the rational truncation of selected amino acid residues is quite rare.…”

“…The truncation of amino acids in the AMP sequence has emerged as a key technique used for AMP modification. Rational truncation of amino acids has a positive effect of reducing hemolysis while maintaining or partly impairing its bioactivity ( Lv et al, 2014 ; Ying et al, 2019 ; He et al, 2020 ; Solstad et al, 2020 ). However, studies on temporin truncation are rare.…”

Modification Strategy of D-leucine Residue Addition on a Novel Peptide from Odorrana schmackeri, with Enhanced Bioactivity and In Vivo Efficacy

“…For example, the MIC of brevinin-1SPb and brevinin-1DYa against the growth of S. aureus was 13 µM and 32 µM with strong haemolysis [ 52 ]. On the other hand, by comparison with other brevinin-1 peptides, such as Ose [ 53 ], brevinin-1H [ 54 ], and B1A [ 55 ], B1OS-D-L showed comparable or even better antibacterial activity against Gram-positive bacteria with a lower level of haemolysis. Researchers have shown that the immune response of waxworms is quite similar to that of mammals [ 56 ].…”

In Vitro & In Vivo Studies on Identifying and Designing Temporin-1CEh from the Skin Secretion of Rana chensinensis as the Optimised Antibacterial Prototype Drug

“…At the same time, some peptides share an amphiphilic character with a hydrophilic surface and a hydrophobic surface [ 6 ]. The bacteria and fungi develop resistance to antibiotics through the reduction of drug permeability to their biomembranes, an efflux of antibiotics molecules from the cell, modification of antimicrobial targets, or enzymatic hydrolysis and degradation [ 7 , 8 , 9 , 10 , 11 , 12 ]. However, an antimicrobial peptide (AMP) inhibits the growth and infection of pathogens through physical destruction or osmosis of the bacterial cell membranes [ 7 ].…”