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

Redrado-Hernandez, SergioMacias-Leon, JavierCastro-Lopez, JorgeDolader, ElenaArias, MaykelGonzalez-Ramirez, Andres ManuelSanchez-Navarro, DavidPetryk, YuliyaFarkas, VladimirVincke, CecileMuyldermans, SergeGarcia-Barbazan, Irenedel Agua, CeliaZaragoza, OscarPardo, JulianGalvez, Eva M.Hurtado-Guerrero, RamonArroyo Nombela, Francisco JavierSanz Santamaría, Ana Belén2026-01-122026-01-122024-08-19Redrado-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.20240582310.1002/anie.202405823https://hdl.handle.net/20.500.14352/129924Invasive 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.engAttribution-NonCommercial-NoDerivatives 4.0 Internationalhttp://creativecommons.org/licenses/by-nc-nd/4.0/Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferasesjournal articlehttp://dx.doi.org/10.1002/anie.202405823open access579Glucanosyltransferasetransglycosilasescell wallnanonobodiesinvasive fungal infectionsMicrobiología (Farmacia)2414 Microbiología2415.01 Biología Molecular de Microorganismos