PhD Defense: Coralie ASSAILLY

Coralie ASSAILLY, PhD student in CEISAM CORAIL team, will defend her thesis entitled “Design and evaluation of multivalent bacterial sialidases inhibitors” on December 18th in CEISAM Marie Curie room.


Sialidases (SAs) are expressed by numerous viruses, bacteria and parasites. The catalytic domain (CAT) of bacterial SAs is often flanked with a lectinic domain (CBM) that allows the enzyme to anchor to a sialoside surface for increasing its catalytic efficiency. In this work, we designed multivalent thiosialosides targeting both the CAT and CBM domains of SAs. The inhibitory activity of the designed sialo-clusters was evaluated on pathogenic SAs from S. pneumoniae (NanA), V. cholerae (VcSA) and T. cruzi (TcTS). Strong synergistic effects were observed between NanA and a synthetic poly-thiosialoside, where each grafted sugar unit has an inhibitory potency up to 3000 times higher than a reference monovalent thiosialoside.

An in-depth study of the binding affinity of the multivalent thiosialosides for NanA and the truncated NanA-CAT and NanA-CBM domains was performed by surface plasmon resonance and by a biochip assay. Insight were provided in the binding mode operating. Then, we developed multivalent compounds based on a more potent inhibitor of the CAT domain, the 2-deoxy-2,3-dehydro-N-acetylneuraminic acid (DANA). Some poly-DANA showed inhibitory levels of the enzymatic activity in the subnanomolar range when assessed against NanA, NanA-CAT or the SA from the commensal bacterium B. thetaiotaomicron (BtSA). Binding assays, molecular modeling studies, and crystallographic experiments suggest that this synergistic interactions probably occurs exclusively in the CAT and not the CBM domain. Altogether, these results suggest the interest of using the concept of multivalency to strongly inhibit the binding potency, and the catalytic activity of pathogenic SAs.

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