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

Thiago Viana de freitas, Utsa Karmakar, Andreanneg. Vasconcelos, Michelea. Santos, Bianca Oliveira do vale lira, Samuelribeiro Costa, Ederalves Barbosa, José Cardozo-Fh, Rafael Correa, Dalilaj.s. Ribeiro, Mauravianna Prates, Kellyg. Magalhães, Marcelohenrique Soller ramada, José Roberto de souza almeida leite, Carlos Bloch, Aline Lima de oliveira, Marc Vendrell, Guilhermedotto Brand

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Article number103056
Pages (from-to)103056
JournalJournal of Biological Chemistry
Volume299
Issue number4
DOIs
Publication statusPublished - 21 Feb 2023

Keywords / Materials (for Non-textual outputs)

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

Fingerprint

Dive into the research topics of 'Release of immunomodulatory peptides at bacterial membrane interfaces as a novel strategy to fight microorganisms'. Together they form a unique fingerprint.

Cite this