Résumé
is a saprophytic fungus and opportunistic pathogen often causing fatal infections in immunocompromised patients. Recently KDNAse, an exoglycosidase hydrolyzing 3-deoxy-D-galacto-D--nonulosonic acid (KDN), a rare sugar from the sialic acid family, was identified and characterized. The principal function of KDNAse is still unclear, but a study suggests a critical role in fungal cell wall morphology and virulence. Potent KDNAse inhibitors are required to better probe the enzyme's biological role and as potential antivirulence factors. In this work, we developed a set of KDNAse inhibitors based on enzymatically stable thio-KDN motifs. C2, C9-linked heterodi-KDN were designed to fit into unusually close KDN sugar binding pockets in the protein. A polymeric compound with an average of 54 KDN motifs was also designed by click chemistry. Inhibitory assays performed on recombinant KDNAse showed a moderate and strong enzymatic inhibition for the two classes of compounds, respectively. The poly-KDN showed more than a nine hundred fold improved inhibitory activity (IC = 1.52 ± 0.37 μM, 17-fold in a KDN molar basis) compared to a monovalent KDN reference, and is to our knowledge, the best synthetic inhibitor described for a KDNase. Multivalency appears to be a relevant strategy for the design of potent KDNase inhibitors. Importantly, poly-KDN was shown to strongly decrease filamentation when co-cultured with at micromolar concentrations, opening interesting perspectives in the development of antivirulence factors.
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@article{pmid38938184,
title = {Multivalent inhibition of the fumigatus KDNase},
author = {Mathieu Scalabrini and Denis Loquet and Camille Rochard and Mélyne Baudin Marie and Coralie Assailly and Yoan Brissonnet and Franck Daligault and Amélie Saumonneau and Annie Lambert and Cyrille Grandjean and David Deniaud and Paul Lottin and Sagrario Pascual and Laurent Fontaine and Viviane Balloy and Sébastien G Gouin},
doi = {10.1039/d4ob00601a},
issn = {1477-0539},
year = {2024},
date = {2024-07-01},
urldate = {2024-07-01},
journal = {Org Biomol Chem},
volume = {22},
number = {28},
pages = {5783--5789},
abstract = { is a saprophytic fungus and opportunistic pathogen often causing fatal infections in immunocompromised patients. Recently KDNAse, an exoglycosidase hydrolyzing 3-deoxy-D-galacto-D--nonulosonic acid (KDN), a rare sugar from the sialic acid family, was identified and characterized. The principal function of KDNAse is still unclear, but a study suggests a critical role in fungal cell wall morphology and virulence. Potent KDNAse inhibitors are required to better probe the enzyme's biological role and as potential antivirulence factors. In this work, we developed a set of KDNAse inhibitors based on enzymatically stable thio-KDN motifs. C2, C9-linked heterodi-KDN were designed to fit into unusually close KDN sugar binding pockets in the protein. A polymeric compound with an average of 54 KDN motifs was also designed by click chemistry. Inhibitory assays performed on recombinant KDNAse showed a moderate and strong enzymatic inhibition for the two classes of compounds, respectively. The poly-KDN showed more than a nine hundred fold improved inhibitory activity (IC = 1.52 ± 0.37 μM, 17-fold in a KDN molar basis) compared to a monovalent KDN reference, and is to our knowledge, the best synthetic inhibitor described for a KDNase. Multivalency appears to be a relevant strategy for the design of potent KDNase inhibitors. Importantly, poly-KDN was shown to strongly decrease filamentation when co-cultured with at micromolar concentrations, opening interesting perspectives in the development of antivirulence factors.},
keywords = {team 2},
pubstate = {published},
tppubtype = {article}
}