Bioinspired Melittin-derived antimicrobial peptides with enhanced selectivity indexes.
RODRIGUES, Lucas Oliveira; NUNES, Letícia Oliveira Catarin; ARAGÃO, Ariani Rodrigues; SURUR, Amanda Koberstain; ARGENTIN, Marcela Nunes; CÂNDIDO, Vitória Tozetti; CASADO, Letícia Rocha; FIAMETTI, Louise Oliveira; BICHO, Gabriel Felipe Hispagnol; CAMARGO, Ilana Lopes Baratella da Cunha; FONTANA, Carla Raquel; VICENTE, Eduardo Festozo; SANTOS FILHO, Norival Alves.
RODRIGUES, Lucas Oliveira; NUNES, Letícia Oliveira Catarin; ARAGÃO, Ariani Rodrigues; SURUR, Amanda Koberstain; ARGENTIN, Marcela Nunes; CÂNDIDO, Vitória Tozetti; CASADO, Letícia Rocha; FIAMETTI, Louise Oliveira; BICHO, Gabriel Felipe Hispagnol; CAMARGO, Ilana Lopes Baratella da Cunha; FONTANA, Carla Raquel; VICENTE, Eduardo Festozo; SANTOS FILHO, Norival Alves.
Abstract: Antimicrobial peptides such as Melittin exhibit potent broad-spectrum activity but are limited by high cytotoxicity. The rational design of bioinspired Melittin-derived analogues represents a promising strategy to reduce toxicity while maintaining antimicrobial efficacy. In this study, Melittin and analogues (TT-1, FKW, and WKW) were synthesized using solid-phase peptide synthesis (SPPS) and characterized for biological and biophysical essays. Antimicrobial and hemolytic activity, serum stability, secondary structure, and membrane interaction were analysed. FKW and WKW exhibited broad-spectrum antimicrobial activity, with minimum inhibitory concentration (MIC) as low as 8 and 16 µg/mL against Staphylococcus aureus and Enterococcus faecium. Both analogues also showed improved activity against Klebsiella pneumoniae (32 µg/mL) and Pseudomonas aeruginosa (128 and 256 µg/mL for FKW and WKW, respectively) compared to Melittin (64 and 512 µg/mL). In terms of cytotoxicity, FKW and WKW showed significantly reduced hemolytic activity, with HC50 values of 264.8 µg/mL and 237.2 µg/mL, respectively, resulting in improved selectivity indexes relative to Melittin (HC50 of 7.9 µg/mL). In liposomes, both adopt a-helical structures and cause disruption via pore formation or detergent-like mechanisms. TT-1 showed minimal toxicity but weak antimicrobial activity (MIC > 256 µg/mL). Although FKW and WKW exhibited limited serum stability (half-lives of 2.2 and 1.5 h), their degradation may reduce systemic toxicity. Overall, these analogues demonstrate an improved balance between antimicrobial activity and safety.
@article={003305736,author = {RODRIGUES, Lucas Oliveira; NUNES, Letícia Oliveira Catarin; ARAGÃO, Ariani Rodrigues; SURUR, Amanda Koberstain; ARGENTIN, Marcela Nunes; CÂNDIDO, Vitória Tozetti; CASADO, Letícia Rocha; FIAMETTI, Louise Oliveira; BICHO, Gabriel Felipe Hispagnol; CAMARGO, Ilana Lopes Baratella da Cunha; FONTANA, Carla Raquel; VICENTE, Eduardo Festozo; SANTOS FILHO, Norival Alves.},title={Bioinspired Melittin-derived antimicrobial peptides with enhanced selectivity indexes},journal={Processes},note={v. 14, n. 10, p. 1630-1-1630-24 + Supplementary Materials},year={2026}}