Deciphering the structure and mechanism of action of computer-designed mastoparan peptides.

Autor:	Oshiro KGN; Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brazil.; S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil.; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil., Freitas CDP; Laboratório de RMN, Instituto de Química, Universidade Federal de Goiás, Goiânia, Brazil., Rezende SB; S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil.; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil., Orozco RMQ; S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil.; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil., Chan LY; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia., Lawrence N; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia., Lião LM; Laboratório de RMN, Instituto de Química, Universidade Federal de Goiás, Goiânia, Brazil., Macedo MLR; Laboratório de Purificação de Proteínas e suas Funções Biológicas, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil., Craik DJ; Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland, Australia., Cardoso MH; Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brazil.; S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil.; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil.; Laboratório de Purificação de Proteínas e suas Funções Biológicas, Universidade Federal de Mato Grosso do Sul, Campo Grande, Brazil., Franco OL; Programa de Pós-Graduação em Patologia Molecular, Faculdade de Medicina, Universidade de Brasília, Brazil.; S-inova Biotech, Programa de Pós-Graduação em Biotecnologia, Universidade Católica Dom Bosco, Campo Grande, Brazil.; Centro de Análises Proteômicas e Bioquímicas, Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brazil.
Jazyk:	angličtina
Zdroj:	The FEBS journal [FEBS J] 2024 Mar; Vol. 291 (5), pp. 865-883. Date of Electronic Publication: 2023 Dec 18.
DOI:	10.1111/febs.17010
Abstrakt:	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. (© 2023 Federation of European Biochemical Societies.)
Databáze:	MEDLINE
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