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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Allosteric Regulation / drug effects
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Amino Acid Sequence
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Animals
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Behavior, Animal / drug effects
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Benzhydryl Compounds / adverse effects
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Benzhydryl Compounds / chemistry
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Benzhydryl Compounds / pharmacology
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Benzhydryl Compounds / therapeutic use
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Biological Assay
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Catalytic Domain
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Cell Line
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Cognition / drug effects*
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Crystallography, X-Ray
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Cyclic Nucleotide Phosphodiesterases, Type 4 / chemistry
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Disease Models, Animal
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Drug Design*
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Humans
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Kinetics
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Mice
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Models, Molecular
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Molecular Sequence Data
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Phenylurea Compounds / adverse effects
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Phenylurea Compounds / chemistry
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Phenylurea Compounds / pharmacology
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Phenylurea Compounds / therapeutic use
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Phosphodiesterase 4 Inhibitors*
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Phosphodiesterase Inhibitors / adverse effects
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Phosphodiesterase Inhibitors / chemistry*
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Phosphodiesterase Inhibitors / pharmacology*
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Phosphodiesterase Inhibitors / therapeutic use
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Protein Structure, Tertiary
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Structure-Activity Relationship
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Vomiting / drug therapy
Substances
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Benzhydryl Compounds
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D159687
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Phenylurea Compounds
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Phosphodiesterase 4 Inhibitors
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Phosphodiesterase Inhibitors
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Cyclic Nucleotide Phosphodiesterases, Type 4