Polyvalent Transition‐State Analogues of Sialyl Substrates Strongly Inhibit Bacterial Sialidases
Résumé
Bacterial sialidases (SA) are validated drug targets expressed by common human pathogens such as Streptococcus pneumoniae, Vibrio cholerae or Clostridium perfringens. Non-covalent inhibitors of bacterial SA capable of reaching the submicromolar level are rarely reported. We developed multi-and polyvalent compounds based on the transition state sialyl cation 2-deoxy-2,3-didehydro-N-acetylneuraminic (DANA). Poly-DANA inhibits the catalytic activity of SA from S. pneumoniae (NanA) and the symbiotic microorganism B. thetaiotaomicron (BtSA) at the picomolar and low nanomolar levels when expressed in moles of molecules and of DANA, respectively. Each DANA grafted to the polymer surpasses the inhibitory potential of the monovalent analogue by more than four orders of magnitude, which represents the highest multivalent effect reported so far for an enzyme inhibition. The synergistic interaction was shown to operate exclusively in the catalytic domain, offering interesting perspectives for the multivalent inhibition of other SA families lacking such as a carbohydrate-binding domain, such as viral, parasitic or human SA.
Domaines
ChimieOrigine | Fichiers produits par l'(les) auteur(s) |
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