Whooping cough is caused by Bordetella pertussis calmodulin-activated adenylyl cyclase (AC) toxin CyaA and still constitutes one of the top five causes of death in young children, particularly in developing countries. Potent and selective CyaA inhibitors would be valuable drugs for the treatment of whooping cough; however, it has been difficult to obtain potent CyaA inhibitors with selectivity relative to mammalian ACs. Geduhn et al. synthesized and tested 32 bulky mono- and bis-anthraniloyl (ANT)-substituted nucleotides as inhibitors of CyaA and mammalian ACs. The bis-Cl-ANTATP inhibited CyaA with a potency ≥ 100-fold higher than mammalian AC1, AC2, and AC5, and bis-MANT-ATP binds to CyaA in the absence of calmodulin. These structure-activity relationship studies demonstrate that substitution on the (M)ANT group results in substantial changes in the pharmacological properties of these compounds. Collectively, these studies have identified the first potent CyaA inhibitor with high selectivity relative to mammalian ACs, showing that the development of selective CyaA inhibitors for the improved treatment of whooping cough is not an elusive goal.
See article at J Pharmacol Exp Ther 2011, 336:104–115.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics