2. Academic Validation
  3. Release of immunomodulatory peptides at bacterial membrane interfaces as a novel strategy to fight microorganisms

Release of immunomodulatory peptides at bacterial membrane interfaces as a novel strategy to fight microorganisms

  • J Biol Chem. 2023 Apr;299(4):103056. doi: 10.1016/j.jbc.2023.103056.
Thiago Viana de Freitas 1,  Utsa Karmakar 2,  Andreanne G Vasconcelos 3,  Michele A Santos 4,  Bianca Oliveira do Vale Lira 5,  Samuel Ribeiro Costa 1,  Eder Alves Barbosa 1,  José Cardozo-Fh 6,  Rafael Correa 7,  Dalila J S Ribeiro 7,  Maura Vianna Prates 6,  Kelly G Magalhães 7,  Marcelo Henrique Soller Ramada 5,  José Roberto de Souza Almeida Leite 3,  Carlos Bloch Jr 6,  Aline Lima de Oliveira 8,  Marc Vendrell 2,  Guilherme Dotto Brand 9
Affiliations

Affiliations

  • 1 Universidade de Brasília, Instituto de Química, Laboratório de Síntese e Análise de Biomoléculas, LSAB, Brasília, Distrito Federal, Brasil.
  • 2 Centre for Inflammation Research, The University of Edinburgh, Edinburgh, UK.
  • 3 Universidade de Brasília, Faculdade de Medicina, Núcleo de Pesquisa em Morfologia e Imunologia Aplicada, NuPMIA, Brasília, Distrito Federal, Brasil.
  • 4 Universidade de Brasília, Instituto de Química, Laboratório de Síntese e Análise de Biomoléculas, LSAB, Brasília, Distrito Federal, Brasil; Universidade de Brasília, Instituto de Química, Laboratório de Ressonância Magnética Nuclear, LRMN, Brasília, Distrito Federal, Brasil.
  • 5 Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília, Brasília, Distrito Federal, Brasil; Programa de Pós-Graduação em Gerontologia, Universidade Católica de Brasília, Brasília, Distrito Federal, Brasil.
  • 6 Laboratório de Espectrometria de Massa, LEM, Embrapa Recursos Genéticos e Biotecnologia, Brasília, Distrito Federal, Brasil.
  • 7 Universidade de Brasília, Instituto de Biologia, Laboratório de Imunologia e Inflamação, LIMI, Brasília, Distrito Federal, Brasil.
  • 8 Universidade de Brasília, Instituto de Química, Laboratório de Ressonância Magnética Nuclear, LRMN, Brasília, Distrito Federal, Brasil.
  • 9 Universidade de Brasília, Instituto de Química, Laboratório de Síntese e Análise de Biomoléculas, LSAB, Brasília, Distrito Federal, Brasil. Electronic address: [email protected].
PMID: 36822328 DOI: 10.1016/j.jbc.2023.103056
Abstract

Cationic and amphiphilic peptides can be used as homing devices to accumulate conjugated Antibiotics to bacteria-enriched sites and promote efficient microbial killing. However, just as important as tackling Bacterial infections, is the modulation of the immune response in this complex microenvironment. In the present report, we designed a peptide chimaera called Chim2, formed by a membrane-active module, an enzyme hydrolysis site and a formyl peptide receptor 2 (FPR2) agonist. This molecule was designed to adsorb onto Bacterial membranes, promote their lysis, and upon hydrolysis by local Enzymes, release the FPR2 agonist sequence for activation and recruitment of immune cells. We synthesized the isolated peptide modules of Chim2 and characterized their biological activities independently and as a single polypeptide chain. We conducted antimicrobial assays, along with Other tests aiming at the analyses of the cellular and immunological responses. In addition, assays using vesicles as models of eukaryotic and prokaryotic membranes were conducted and solution structures of Chim2 were generated by 1H NMR. Chim2 is antimicrobial, adsorbs preferentially to negatively charged vesicles while adopting an α-helix structure and exposes its disorganized tail to the solvent, which facilitates hydrolysis by tryptase-like Enzymes, allowing the release of the FPR2 agonist fragment. This fragment was shown to induce accumulation of the cellular activation marker, lipid bodies, in mouse macrophages and the release of immunomodulatory interleukins. In conclusion, these data demonstrate that peptides with antimicrobial and immunomodulatory activities can be considered for further development as drugs.

Keywords

antibiotics; antimicrobial peptide (AMP); drug design; immunology; inflammation; nuclear magnetic resonance (NMR); pattern recognition receptor (PRR); peptide chemical synthesis.

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