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

Nature Biotechnology volume 28, pages 6370 (2010) | Download Citation

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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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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.

Author information

Author notes

    • Alex B Burgin
    •  & Olafur T Magnusson

    These authors contributed equally to this work.

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.

Competing interests

The authors are employees of deCODE genetics, Inc. or subsidiaries thereof.

Corresponding authors

Correspondence to Alex B Burgin or Mark E Gurney.

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DOI

https://doi.org/10.1038/nbt.1598

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