RT Journal Article
T1 Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferases
A1 Redrado-Hernandez, Sergio
A1 Macias-Leon, Javier
A1 Castro-Lopez, Jorge
A1 Dolader, Elena
A1 Arias, Maykel
A1 Gonzalez-Ramirez, Andres Manuel
A1 Sanchez-Navarro, David
A1 Petryk, Yuliya
A1 Farkas, Vladimir
A1 Vincke, Cecile
A1 Muyldermans, Serge
A1 Garcia-Barbazan, Irene
A1 del Agua, Celia
A1 Zaragoza, Oscar
A1 Pardo, Julian
A1 Galvez, Eva M.
A1 Hurtado-Guerrero, Ramon
A1 Arroyo Nombela, Francisco Javier
A1 Sanz Santamaría, Ana Belén
AB 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.
PB Wiley
YR 2024
FD 2024-08-19
LK https://hdl.handle.net/20.500.14352/129924
UL https://hdl.handle.net/20.500.14352/129924
LA eng
NO Redrado-Hernández, S., Javier Macías-León, J., Castro-López, J., Sanz, AB , Dolader,E., Arias, M., González-Ramírez, AM., Sánchez-Navarro, D., Petryk, J., Farkaš, V., Vincke, C., Muyldermans, S., García-Barbazán, I., Del Agua, C., Zaragoza, O., Arroyo, J., Pardo, J., Gálvez, EM., Hurtado-Guerrero, R.Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferases. Angew Chem Int Ed Engl. 2024 Aug 19;63(34):e202405823. doi: 10.1002/anie.202405823
NO Ministerio de Ciencia e Innovación y Universidades (España)
NO Instituto de Saludo Carlos III (CIBERINFEC) (España)
NO Vedecka grantova agentura MSVVaS SR a SAV (VEGA)
NO Fundación Agencia Aragonesa para la Investigación y el Desarrollo (ARAID) (España)
NO Comunidad de Madrid
DS Docta Complutense
RD 20 ene 2026