Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety.
Nat Biotechnol
; 28(1): 63-70, 2010 Jan.
Article
in En
| MEDLINE
| ID: mdl-20037581
ABSTRACT
Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Phosphodiesterase Inhibitors
/
Drug Design
/
Cognition
/
Phosphodiesterase 4 Inhibitors
Limits:
Animals
/
Humans
Language:
En
Journal:
Nat Biotechnol
Journal subject:
BIOTECNOLOGIA
Year:
2010
Document type:
Article
Affiliation country: