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MAP-2:CD55 chimeric construct effectively modulates complement activation.
González-Del-Barrio, Lydia; Pérez-Alós, Laura; Cyranka, Leon; Rosbjerg, Anne; Nagy, Simon; Prohászka, Zoltán; Garred, Peter; Bayarri-Olmos, Rafael.
Afiliação
  • González-Del-Barrio L; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • Pérez-Alós L; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • Cyranka L; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • Rosbjerg A; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
  • Nagy S; Recombinant Protein and Antibody Unit, Copenhagen University Hospital, Rigshospitalet, Denmark.
  • Prohászka Z; Research Laboratory, Department of Internal Medicine and Hematology, and MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
  • Garred P; Research Laboratory, Department of Internal Medicine and Hematology, and MTA-SE Research Group of Immunology and Hematology, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
  • Bayarri-Olmos R; Laboratory of Molecular Medicine, Department of Clinical Immunology, Section 7631, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
FASEB J ; 37(11): e23256, 2023 11.
Article em En | MEDLINE | ID: mdl-37823685
The complement system is a complex, tightly regulated protein cascade involved in pathogen defense and the pathogenesis of several diseases. Thus, the development of complement modulators has risen as a potential treatment for complement-driven inflammatory pathologies. The enzymatically inactive MAP-2 has been reported to inhibit the lectin pathway by competing with its homologous serine protease MASP-2. The membrane-bound complement inhibitor CD55 acts on the C3/C5 convertase level. Here, we fused MAP-2 to the four N-terminal domains of CD55 generating a targeted chimeric inhibitor to modulate complement activation at two different levels of the complement cascade. Its biological properties were compared in vitro with the parent molecules. While MAP-2 and CD55 alone showed a minor inhibition of the three complement pathways when co-incubated with serum (IC50MAP-2+CD55 1-4 = 60.98, 36.10, and 97.01 nM on the classical, lectin, and alternative pathways, respectively), MAP-2:CD551-4 demonstrated a potent inhibitory activity (IC50MAP-2:CD55 1-4 = 2.94, 1.76, and 12.86 nM, respectively). This inhibitory activity was substantially enhanced when pre-complexes were formed with the lectin pathway recognition molecule mannose-binding lectin (IC50MAP-2:CD55 1-4 = 0.14 nM). MAP-2:CD551-4 was also effective at protecting sensitized sheep erythrocytes in a classical hemolytic assay (CH50 = 13.35 nM). Finally, the chimeric inhibitor reduced neutrophil activation in full blood after stimulation with Aspergillus fumigatus conidia, as well as phagocytosis of conidia by isolated activated neutrophils. Our results demonstrate that MAP-2:CD551-4 is a potent complement inhibitor reinforcing the idea that engineered fusion proteins are a promising design strategy for identifying and developing drug candidates to treat complement-mediated diseases.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas do Sistema Complemento / Ativação do Complemento Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas do Sistema Complemento / Ativação do Complemento Limite: Animals Idioma: En Ano de publicação: 2023 Tipo de documento: Article