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Safer Alzheimer's drugs?

PSI-SGKB [doi:10.1038/fa_psisgkb.2010.07]
Featured Article - March 2010
Short description: Inhibitors that only partially block phosphodiesterase activity look likely to reduce the nasty side effects of full inhibitors.

The PDE4 enzyme can exist in multiple conformations with UCR2 (green) or C-terminal (yellow) regulatory helices allowing access (“open”) or blocking access (“closed”) to the active site. In the model, movement of regulatory helices is affected by phosphorylation states of the enzyme and by the presence of partner proteins. For more details see Nature Biotech 28, 63–70, 2010.

Phosphodiesterase 4 (PDE4) is a promising drug target, and could be useful for the treatment of central nervous system, inflammatory and respiratory diseases.

But no approved drugs are yet available, as candidate drugs are not well tolerated and often cause vomiting and diarrhea, an effect that seems to be triggered by the noradrenergic pathway in the brainstem.

A team from deCODE led by Mark Gurney and Alex Burgin think they have a solution. They established the structure of PDE4 in complex with various inhibitors, and inspired by these designed a small-molecule PDE4 blocker which causes less vomiting in animal models while still retaining biological activity.

In Nature Biotechnology, they present seven co-crystal structures of part of the regulatory domain of one of the PDE4 isoforms, PDE4D, with inhibitors bound 1 . They used Gene Composer 2, 3 software, a suite of programs developed through the work of PSI center ATGC3D to design suitable protein constructs for crystallization.

From these structures, they realized that the upstream conserved region 2 (UCR2), which forms a regulatory module with upstream conserved region 1 (UCR1), 'closes' the active site in the absence of protein kinase A phosphorylation and 'opens' it once phosphorylated.

It was clear that the key to PDE4D regulation was controlling access to the active site. Gurney and Burgin's teams reasoned that if activity was only partially inhibited, toxicity might be reduced.

They explored the structure–activity relationship of PDE4D with various inhibitors, and found some compounds that did not totally block phosphodiesterase activity. By making systematic chemical changes they were able to produce over 100 partial inhibitors, and solved over 20 co-crystal structures of the compounds in complex with PDE4D.

To test the effects of these inhibitors, they used cellular and animal models. Their results show that the partial inhibitors have much less effect on the cAMP signaling induced by PDE4D and reduce the likelihood of causing vomiting.

This approach is likely to be useful for the design of drugs to treat Alzheimer's disease, Huntington's disease, schizophrenia and depression.

A similar approach has been described previously for allosteric modulators of G-protein-coupled receptors and for atypical retinoid ligands of nuclear hormone receptors.

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References

  1. A. B. Burgin et al. Design of phosphodiesterase 4D (PDE4) allosteric modulators for enhancing cognition with improved safety.
    Nature Biotechnol. 28, 63-70 (2010). doi:10.1038/nbt.1598

  2. Gene Composer: Database Software for Protein Construct Design, Codon Engineering, and Gene Synthesis.
    9, 36 (2009).

  3. Raymond et al. Combined Protein Construct and Synthetic Gene Engineering for Heterologous Protein Expression and Crystallization using Gene Composer.
    9, 37

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health