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00925njm 22002777a 4500 dc Redrado-Hernández, Sergio author Macías-León, Javier author Castro-López, Jorge author Belén Sanz, Ana author Dolader, Elena author Arias, Maykel author González-Ramírez, Andrés Manuel author Sánchez-Navarro, David author Petryk, Yuliya author Farkaš, Vladimír author Vincke, Cécile author Muyldermans, Serge author Garcia-Barbazan, Irene author Del Agua, Celia author Zaragoza, Oscar author Arroyo, Javier author Pardo, Julián author Gálvez, Eva M author Hurtado-Guerrero, Ramon author Redrado-Hernández, Sergio author Macías-León, Javier author Castro-López, Jorge author Belén Sanz, Ana author Dolader, Elena author Arias, Maykel author González-Ramírez, Andrés Manuel author Sánchez-Navarro, David author Petryk, Yuliya author Farkaš, Vladimír author Vincke, Cécile author Muyldermans, Serge author Del Agua, Celia author Zaragoza, Oscar author Arroyo, Javier author Pardo, Julián author Gálvez, Eva M author Hurtado-Guerrero, Ramon author 2024-08-19 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. Angew Chem Int Ed Engl. 2024 Aug 19;63(34):e202405823. 1521-3773 1433-7851 10.1002/anie.202405823 Angewandte Chemie 38856634 https://hdl.handle.net/20.500.12105/25091 Glucanosyltransferases Cell wall Invasive fungal infections Nanobodies Transglycosylases Broad Protection against Invasive Fungal Disease from a Nanobody Targeting the Active Site of Fungal β-1,3-Glucanosyltransferases