Deciphering the structure and mechanism of action of computer‐designed mastoparan peptides

Abstract

Mastoparans are cationic peptides with multifunctional pharmacological properties. Mastoparan‐R1 and mastoparan‐R4 were computationally designed based on native mastoparan‐L from wasps and have improved therapeutic potential for the control of bacterial infections. Here, we evaluated whether these peptides maintain their activity against Escherichia coli strains under a range of salt concentrations. We found that mastoparan‐R1 and mastoparan‐R4 preserved their activity under the conditions tested, including having antibacterial activities at physiological salt concentrations. The overall structure of the peptides was investigated using circular dichroism spectroscopy in a range of solvents. No significant changes in secondary structure were observed (random coil in aqueous solutions and α‐helix in hydrophobic and anionic environments). The three‐dimensional structures of mastoparan‐R1 and mastoparan‐R4 were elucidated through nuclear magnetic resonance spectroscopy, revealing amphipathic α‐helical segments for Leu3‐Ile13 (mastoparan‐R1) and Leu3‐Ile14 (mastoparan‐R4). Possible membrane‐association mechanisms for mastoparan‐R1 and mastoparan‐R4 were investigated through surface plasmon resonance and leakage studies with synthetic POPC and POPC/POPG (4:1) lipid bilayers. Mastoparan‐L had the highest affinity for both membrane systems, whereas the two analogs had weaker association, but improved selectivity for lysing anionic membranes. This finding was also supported by molecular dynamics simulations, in which mastoparan‐R1 and mastoparan‐R4 were found to have greater interactions with bacteria‐like membranes compared with model mammalian membranes. Despite having a few differences in their functional and structural profiles, the mastoparan‐R1 analog stood out with the highest activity, greater bacteriostatic potential, and selectivity for lysing anionic membranes. This study reinforces the potential of mastoparan‐R1 as a drug candidate.

Antiviral Activities of Mastoparan-L-Derived Peptides against Human Alphaherpesvirus 1

“…A rich source of antiviral peptides is the venom of certain animals, such as arthropods. Initially isolated from wasp venom, the peptide mast-L has proven to be a promising template for designing new peptides [ 22 , 23 , 37 , 38 ]. The initial assays with the peptides were performed to determine cell viability and the MNTC (CC 20 —Cytotoxic Concentration for 20% of the cell monolayer or 80% of cell viability).…”

In silico optimization of analogs derived pro‐adrenomedullin peptide to evaluate antimicrobial potential

“…Then, for some peptides, it has been shown that the stabilization of the helical structure plays a primary role in their antibacterial activities (Torres et al, 2018). However, for others, it is the balance between hydrophobicity and the insertion of positive residues on the hydrophilic face rather than the adoption of a helical structure that has a more significant effect on its biological activities (Oshiro et al, 2024;. All this shows the complexity of the delicate balance required between physicochemical properties and structure for the biological activities of AMPs, despite the advances made in the AMPs field and the countless studies of the structure-activity relationship (Edwards et al, 2016;.…”