Structural insights from neuraminidase diversity: Implications for selectivity in anti-infective and anticancer strategies.

Neuraminidases (NAs) are glycoside hydrolase enzymes pivotal in carbohydrate metabolism, ubiquitously present in viruses, bacteria, fungi, and mammals. These enzymes catalyze the cleavage of terminal sialic acid residues from glycoproteins and glycolipids, impacting various biological processes, including pathogen infections and cancer cell proliferation. In our study, we employed advanced in silico strategies to repurpose existing drugs, aiming to provide a rapid response to health emergencies posed by multi-drug-resistant bacteria and fungi, as well as expanding the arsenal of antiviral therapies. Phylogenetic and structural superimposition analyses revealed four principal NA clusters, grouping viral, bacterial, fungal, and metazoa NAs. Comprehensive sequence and structural analyses identified three conserved binding regions across diverse species. The first binding region, observed in NAs crystallized with 23 different small molecules from viruses, fungi, bacteria, and metazoa, consists of three contact points hosting a basic RR dipeptide or RRN tripeptide, a basic/acidic R[E/D] dipeptide, and a basic/aromatic RY dipeptide involved in substrate/inhibitors binding. A second binding pocket was highlighted by comparing a group of NAs sampled from metazoa, fungi, and bacteria, crystallized in complex with 4 small molecules. The third binding pocket was proposed based on a fungal NA crystallized in complex with 1 small molecule. These identified binding pockets are proposed for being targettable by selective inhibitors of species-specific NAs, suggesting new avenues for anti-infective and anticancer strategies.