Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferases.

Autor: Redrado-Hernández S; Instituto de Carboquímica ICB-CSIC, 50018, Zaragoza, Spain.; Center for Biomedical Research in Network in Infectious Diseases (CIBERINFEC), Health Institute Carlos III, 28029, Madrid, Spain., Macías-León J; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018, Zaragoza, Spain., Castro-López J; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018, Zaragoza, Spain., Belén Sanz A; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040, Madrid, Spain., Dolader E; Department of Microbiology, Pediatry, Radiology and Public Health, University of Zaragoza, 50009, Zaragoza, Spain.; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, Spain., Arias M; Center for Biomedical Research in Network in Infectious Diseases (CIBERINFEC), Health Institute Carlos III, 28029, Madrid, Spain.; Department of Microbiology, Pediatry, Radiology and Public Health, University of Zaragoza, 50009, Zaragoza, Spain.; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, Spain., González-Ramírez AM; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018, Zaragoza, Spain., Sánchez-Navarro D; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018, Zaragoza, Spain., Petryk Y; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040, Madrid, Spain., Farkaš V; Department of Glycobiology, Institute of Chemistry, Center for Glycomics, Slovak Academy of Sciences, 84538, Bratislava, Slovakia., Vincke C; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050, Brussels, Belgium., Muyldermans S; Laboratory of Cellular and Molecular Immunology, Vrije Universiteit Brussel, 1050, Brussels, Belgium., García-Barbazán I; Mycology Reference Laboratory. National Centre for Microbiology., Health Institute Carlos III, 28220, Majadahonda, Madrid, Spain., Del Agua C; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, Spain.; Department of Pathology, Hospital Clínico Universitario Lozano Blesa, IIS-Aragón, 50009, Zaragoza, Spain., Zaragoza O; Center for Biomedical Research in Network in Infectious Diseases (CIBERINFEC), Health Institute Carlos III, 28029, Madrid, Spain.; Mycology Reference Laboratory. National Centre for Microbiology., Health Institute Carlos III, 28220, Majadahonda, Madrid, Spain., Arroyo J; Departamento de Microbiología y Parasitología, Facultad de Farmacia, Universidad Complutense de Madrid, 28040, Madrid, Spain., Pardo J; Center for Biomedical Research in Network in Infectious Diseases (CIBERINFEC), Health Institute Carlos III, 28029, Madrid, Spain.; Department of Microbiology, Pediatry, Radiology and Public Health, University of Zaragoza, 50009, Zaragoza, Spain.; Aragón Health Research Institute (IIS Aragón), Biomedical Research Centre of Aragón (CIBA), 50009, Zaragoza, Spain., Gálvez EM; Instituto de Carboquímica ICB-CSIC, 50018, Zaragoza, Spain.; Center for Biomedical Research in Network in Infectious Diseases (CIBERINFEC), Health Institute Carlos III, 28029, Madrid, Spain., Hurtado-Guerrero R; Institute of Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza, Mariano Esquillor s/n, Campus Rio Ebro, Edificio I+D, 50018, Zaragoza, Spain.; Fundación ARAID, 50018, Zaragoza, Spain.; Copenhagen Center for Glycomics, Department of Cellular and Molecular Medicine, University of Copenhagen, DK-2200, Copenhagen, Denmark.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2024 Aug 19; Vol. 63 (34), pp. e202405823. Date of Electronic Publication: 2024 Jul 22.
DOI: 10.1002/anie.202405823
Abstrakt: Invasive fungal disease accounts for about 3.8 million deaths annually, an unacceptable rate that urgently prompts the discovery of new knowledge-driven treatments. We report the use of camelid single-domain nanobodies (Nbs) against fungal β-1,3-glucanosyltransferases (Gel) involved in β-1,3-glucan transglycosylation. Crystal structures of two Nbs with Gel4 from Aspergillus fumigatus revealed binding to a dissimilar CBM43 domain and a highly conserved catalytic domain across fungal species, respectively. Anti-Gel4 active site Nb3 showed significant antifungal efficacy in vitro and in vivo prophylactically and therapeutically against different A. fumigatus and Cryptococcus neoformans isolates, reducing the fungal burden and disease severity, thus significantly improving immunocompromised animal survival. Notably, C. deneoformans (serotype D) strains were more susceptible to Nb3 and genetic Gel deletion than C. neoformans (serotype A) strains, indicating a key role for β-1,3-glucan remodelling in C. deneoformans survival. These findings add new insight about the role of β-1,3-glucan in fungal biology and demonstrate the potential of nanobodies in targeting fungal enzymes to combat invasive fungal diseases.
(© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)
Databáze: MEDLINE
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