Titre:	Rational design of Chim3, a multifunctional peptide carrying a formyl peptide receptor 2 (FPR2) agonist module released by bacterial signal peptidase I (Spase I)
Auteur(s):	Costa, Samuel Ribeiro Lira, Bianca O. Calixto, Gabriel Felipe Gomes Nunes, João Bueno Machado, Sabrina Azevedo Vasconcelos, Andreanne Gomes Lourenço, Ana L. P. Sousa, Thaís Campos de Goncalves, Sónia Murad, Andre Melro Santos, Nuno C. Leite, José Roberto de Souza de Almeida Magalhães, Kelly Grace Ramada, Marcelo S. Brand, Guilherme Dotto
metadata.dc.identifier.orcid:	https://orcid.org/0009-0004-7098-3628 https://orcid.org/0000-0002-9651-1598 https://orcid.org/0000-0002-1615-0009
metadata.dc.contributor.affiliation:	Universidade de Brasília, Instituto de Química, Laboratório de Síntese e Análise de Biomoléculas (LSAB) Universidade Católica de Brasília, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia Universidade de Brasília, Instituto de Biologia, Departamento de Biologia Celular, Laboratório de Imunologia e Inflamação (LIMI) Universidade de Brasília, Instituto de Química, Laboratório de Síntese e Análise de Biomoléculas (LSAB) Universidade de Brasília, Instituto de Biologia, Departamento de Biologia Celular, Laboratório de Imunologia e Inflamação (LIMI) Universidade de Brasília, Campus Universitário Darcy Ribeiro, Faculdade de Medicina, Núcleo de Pesquisa em Morfologia e Imunologia Aplicada (NuPMIA) Universidade Católica de Brasília, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia Universidade Católica de Brasília, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia Gulbenkian Institute for Molecular Medicine (GIMM) Universidade de Lisboa, Faculdade de Medicina Embrapa Recursos Geneticos e Biotecnologia, Laboratorio de Espectrometria de Massa (LEM) Gulbenkian Institute for Molecular Medicine (GIMM) Universidade de Lisboa, Faculdade de Medicina Universidade de Brasília, Campus Universitário Darcy Ribeiro, Faculdade de Medicina, Núcleo de Pesquisa em Morfologia e Imunologia Aplicada (NuPMIA) Universidade de Brasília, Instituto de Biologia, Departamento de Biologia Celular, Laboratório de Imunologia e Inflamação (LIMI) Universidade Católica de Brasília, Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia Universidade Católica de Brasília, Programa de Pós-Graduação em Gerontologia
Date de publication:	12-mar-2025
Editeur:	Federation of European Biochemical Societies (FEBS)
Référence bibliographique:	COSTA, Samuel Ribeiro et al. Rational design of Chim3, a multifunctional peptide carrying a formyl peptide receptor 2 (FPR2) agonist module released by bacterial signal peptidase I (Spase I). FEBS Journal, [S. l.], v. 292, 12, 2025. DOI: https://doi.org/10.1111%2Ffebs.70055. Disponível em: https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.70055. Acesso em: 24 fev. 2026.
Abstract:	Membrane-active peptides are useful tools in the design of multifunctional molecules. For example, peptide chimeras may release, after proteolysis of membrane-adsorbed molecules, pharmacologically active fragments. In previous work, Chim2, an antimicrobial peptide composed of a membrane-active module, an enzymatic hydrolysis site, and an agonist moiety for type 2 formyl peptide receptors (FPR2), was conceptualized. Based on Chim2, a peptide named Chim3 was designed, adding a consensus sequence for the bacterial signal peptidase I (Spase I). Spase I is a protease located in an extracytoplasmic face of Gram-positive and Gram-negative bacterial membranes and is essential for protein export. Chim3 was synthesized and its activity as an antimicrobial agent was determined. In addition, Chim3 was incubated with Escherichia coli and Staphylococcus aureus, and peptide hydrolysis products were evaluated by LC–MS/MS. Data demonstrate that Chim3 has potent antimicrobial activity. After incubation with bacteria, Chim3 underwent intense hydrolysis. Proteolysis was detected in the Chim3 Spase I consensus sequence after incubation with both bacteria, and the release of the FPR2 agonist segment was observed. The synthesis of an improved structure of Chim3 with N-methyl tyrosine in the FPR2 agonist segment was performed, resulting in CHIM3Y-NMe. This modification caused significantly higher concentrations of the FPR2 agonist portion arising from the modified peptide after incubation assays with E. coli. The modified FPR2 agonist WK(Y-NMe)M-NH2 interacted with the mouth region of FPR2 and induced the release of TNF-α and IL-6 in mouse macrophages, making CHIM3Y-NMe an interesting antimicrobial and immunomodulatory molecule for further development aimed at in vivo application.
DOI:	https://doi.org/10.1111/febs.70055
metadata.dc.relation.publisherversion:	https://febs.onlinelibrary.wiley.com/doi/10.1111/febs.70055
Collection(s) :	Artigos publicados em periódicos e afins

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