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

Sergio Redrado-Hernández, Javier Macías-León, Jorge Castro-López, Ana Belén Sanz, Elena Dolader, Maykel Arias, Andrés Manuel González-Ramírez, David Sánchez-Navarro, Yuliya Petryk, Vladimir Farkaš, Cecile Vincke, Serge Muyldermans, Irene García-Barbazán, Celia Del Agua, Oscar Zaragoza, Javier Arroyo, Julián Pardo, Eva Gálvez, Ramon Hurtado-Guerrero

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article numbere202405823
Pages (from-to)1-15
Number of pages15
JournalAngewandte Chemie International Edition
Volume63
Issue number34
DOIs
Publication statusPublished - 19 Aug 2024

Bibliographical note

© 2024 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

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