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Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety

Nature Biotechnology volume 28, pages 63–70 (2010)Cite this article

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 (Imax ∼ 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.

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Figure 1: PDE4D Constructs.
Figure 2: Capping the active site by UCR2.
Figure 3: A common pharmacophore for PDE4 inhibitors accessing the UCR2 binding pose.
Figure 4: Critical pharmacophore elements that determine partial kinetic behavior of PDE4 allosteric modulators.
Figure 5: Effects of compounds on mouse models of cognition and a behavioral correlate of emesis.
Figure 6: Effects of compounds on emesis.
Figure 7: A model to explain how PDE4 regulatory domains control PDE4 activity.

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Acknowledgements

The development of Gene Composer software used to design protein constructs was supported in part by the National Institute of General Medical Sciences–National Center for Research Resources, co-sponsored PSI-2 Specialized Center Grant U54 GM074961 for the Accelerated Technologies Center for Gene to 3D Structure. The authors would like to thank M. Smith, M.H. Haraldsson, G.V. Halldorsdottir, B.B. Sigurdsson, G. Bragason, I. Saemundsdottir, B. Gudmundsdottir, T.J. Dagbjartsdottir, K. Astradsdottir, S. Gunnarsdottir, B. Eiriksdottir, N. Zhou, D. Sullins, P. Rauen, A. Motta, W. Zeller, J. Christensen and M. O'Connell for contributions to the research. We also thank Dr. Akira Ito and colleagues at Dainippon Sumitomo and Dr. Klaus Mendla and colleagues at Boerhinger Ingelheim for contributions to the animal studies.

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  1. Alex B Burgin and Olafur T Magnusson: These authors contributed equally to this work.

  2. mgurney@decode.com

Authors and Affiliations

  1. deCODE biostructures, Bainbridge Island, Washington, USA

    Alex B Burgin, Pam Witte, Bart L Staker & Lance J Stewart

  2. deCODE genetics, Reykjavik, Iceland

    Olafur T Magnusson, Jon M Bjornsson, Margret Thorsteinsdottir, Sigrun Hrafnsdottir & Mark E Gurney

  3. deCODE chemistry, Woodridge, Illinois, USA

    Jasbir Singh, Timothy Hagen & Alex S Kiselyov

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Contributions

A.B.B., P.W., B.L.S., L.J.S. and M.E.G. contributed to the structural and molecular biology experiments. O.T.M., J.M.B, M.T., S.H. and M.E.G. contributed to kinetic, safety and efficacy studies. J.S., T.H., A.S.K. and M.E.G. contributed to medicinal chemistry experiments. A.B.B. and M.E.G. wrote the manuscript.

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Correspondence to Alex B Burgin or Mark E Gurney.

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Burgin, A., Magnusson, O., Singh, J. et al. Design of phosphodiesterase 4D (PDE4D) allosteric modulators for enhancing cognition with improved safety. Nat Biotechnol 28, 63–70 (2010). https://doi.org/10.1038/nbt.1598

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