Pharmacology of ADP-ribosylation

Authors


Abstract

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ADP-ribosyltransferase ARTD1/PARP1 is a target for cancer and ischemia drug development. Several other ARTD-family enzymes have been characterized in recent years, and it has become clear that their inhibition might also have therapeutic value. This minireview series summarizes current knowledge of pharmacological inhibition of ADP-ribosyltransferases by a compound class called PARP inhibitors and the prospects for drug development.

ADP-ribosylation of proteins is emerging as a very versatile post-translational modification in various signaling pathways. Poly-ADP-ribosylation, with the massive charge accumulation that it confers, breaks up chromatin structure by interfering with protein–DNA interactions, and alters the surface properties of substrate proteins. Mono-ADP-ribosylation alters the chemistry of specific protein side chains, provides a handle for binding of a specific recognition or recruiting domain, or acts as a destruction mark on a protein substrate. Currently various new functional aspects are being revealed, and new therapeutic opportunities are emerging. Novel poly-ADP-ribose polymerase (PARP) inhibitors and other research tools are being developed that exploit the well-established inhibition of ARTD1/PARP1, particularly in development of therapeutic agents for cancer and ischemia.

Recently, at a Special Interest Symposium held within the framework of the EMBO 2012 meeting, European researchers met to disseminate their latest results on this theme. Two series of minireviews are presented that provide a cross-section of these studies: this series places emphasis on aspects of drug target identification and pharmacology, while an accompanying series focuses on the physiological aspects of ADP-ribosylation (Koch-Nolte F and Ziegler M (2013) FEBS J 280, 3483).

As our understanding of ADP-ribosylation in general grows, so does the scope of pathways of potential therapeutic interest. In the cytosol of mammalian cells, ADP-ribosylation is mediated by enzymes with a diphtheria toxin-homology ADP-ribosyltransferase domain, the ARTD family. Scarpa et al. review the state of knowledge on these enzymes, and discuss their relationship with disease mechanisms, particularly cancer. Among the ARTD family members, the tankyrases (ARTD5 and ARTD6) have clearly distinct cellular roles. Lehtiö et al. review the tankyrase functions in processes such as glucose metabolism and Wnt signaling, and describe current tankyrase inhibitors in atomic detail and with regard to their potential as research tools and in therapeutics development. Small-compound inhibitors are the main topic of the review by Ekblad et al., who give a historical overview of current clinical PARP inhibitors, and summarize recent structural information to discuss possible routes toward development of selective inhibitors. In their review, Menzel et al. discuss specific inhibitors of a different sort – nanobodies. They give a historical perspective on the generation, structure and application of this type of renewable antibody, and discuss their use in research and their potential in the clinic.

Biographies

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    Herwig Schüler is an Associate Professor of Structural Biology at the Karolinska Institutet in Stockholm (Sweden). Research in his laboratory is focused on the structural and biochemical characterization of protein domains involved in ADP-ribosylation, and the development of selective inhibitors for human ADP-ribosyltransferases.

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    Mathias Ziegler is a Professor of Molecular Biology at the University of Bergen (Norway). His major research interests are related to NAD-related processes, with particular emphasis on the biosynthesis, signaling pathways and subcellular compartmentation of the pyridine nucleotides.

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