Biology Department Seminar

Cyclic nucleotide phosphodiesterases (PDEs) are key enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. Family selective PDE inhibitors have been widely studied as therapeutics for treatment of various human diseases. The most successful example of this drug class is the PDE5 inhibitor sildenafil (Viagra) that has been used for treatment of male erectile dysfunction and pulmonary hypertension. Over hundred of PDE isoforms encoded by 21 human genes contain a conserved catalytic domain, but possess different substrate specificity and inhibitor selectivity. This talk will focus on the structural implications on the substrate specificity and inhibitor selectivity of PDE families and structure-based design of PDE4 selective inhibitors for treatment of inflammatory diseases. The structures of PDE10 and PDE4 in complex with the substrates cAMP and cGMP suggest that these substrates are recognized by different orientations and interactions and therefore provide direct evidence against the widely circulated mechanism of “glutamine switch”. PDE5 shows multiple conformations of the H-loop upon binding of the inhibitors. The different conformations of vardenafil (Levitra) and sildenafil form the structural basis for their physiological behaviors. The structure-based design has led to a discovery of a novel type of PDE4 inhibitors. The best one is very potent in anti-inflammation and inhibits the TNFα release 10-fold better than cilomilast that is a GSK drug-lead in phase III clinic trial for treatment of chronic obstructive pulmonary disease.