Alternatives to PDE4 Catalytic Site Inhibitors

PDE4 enzymes have been the subject of extensive research because of the therapeutic potential of PDE4 inhibitors to treat a number of major disease areas. However, PDE4 inhibitors have been slow to fulfill this therapeutic potential because their use is associated with dose-limiting side effects such as nausea and vomiting. Despite concerted efforts to refine PDE4 inhibitors in order to improve efficacy and minimize side effects, current inhibitors are still largely non-selective. The universal inhibition of all PDE4 activity by non-selective inhibitors is undoubtedly a major factor in the generation of unpleasant side effects. The development of subtype and isoform selective inhibitors is therefore desirable in an effort to overcome the clinical limitations of non-selective inhibitors. The interest in sub-family selective inhibitors has only been heightened by studies, including those in knockout mice, that suggest that inhibition of PDE4B is associated with the anti-inflammatory and immunomodulatory effects of PDE4 inhibitors, while inhibition of PDE4D is linked to anti-depressant effects, enhanced cognition, memory and also emesis (Jin et al. 2007; Zhang and

O'Donnell 2007). The design of highly selective inhibitors is, however, very difficult due to the fact that the catalytic sites of all the PDE4 sub-families are very similar. Ironically, the most progress has been made towards the development of PDE4D-specific inhibitors (Giembycz 2001) when it is inhibition of this sub-family that is suggested to be responsible for the emetic effect of PDE4 inhibitors (Robichaud et al. 2002). The development of isoform-specific inhibitors may help to dissect out the desirable psychopharmacological effects of PDE4D inhibitors from the undesirable emetic effects. However, PDE4 isoforms within a sub-family have identical catalytic sites, so conventional drug design targeted to the catalytic site cannot be used to distinguish between them. Overcoming the problems of isoform-specific inhibition will therefore require novel approaches and technologies.

Isoform-specific inhibition has been achieved, for the first time, in cultured cells by the use of small interfering RNA (siRNA) directed towards PDE4D3 and PDE4D5 (Lynch et al. 2005). In this manner, PDE4D5 was identified as the functionally important PDE4 species that interacts with P-arrestin to control the PKA/AKAP79-mediated switching of the P2AR to activation of the ERK pathway. The results of this study elegantly demonstrate that particular PDE4 isoforms can have very specific, non-redundant, functional roles, such that loss of the isoform gives rise to a phenotype. While this illuminates the potential therapeutic benefits of isoform-specific inhibition, the siRNA approach does not easily translate to the clinic. Future research into PDE4 iso-form-specific inhibitors should perhaps then focus on the specific interactions and regulatory mechanisms of particular PDE4 isoforms. This offers two potential routes of new drug design, one being to design novel inhibitors that can recognize the catalytic site of a specific isoform as it adopts a particular conformation mediated by its protein-protein interactions and regulatory phosphorylations. The second route is to develop compounds that do not target the catalytic site, but that instead ablate the function of a PDE4 isoform by disrupting its protein-protein interactions. This route is made more possible by the increasing knowledge of PDE4 protein-protein interactions and in particular the detailed information that can be gained from peptide array technology (see Sect. 3.1). Proof of principle for such an approach has recently been provided through the development of cell-permeable peptides able to disrupt PDE4/ DISC1 interactions, PDE4D5/RACK1 and PDE4D5/barrestin in living cells (Murdoch et al. 2007; Smith et al. 2007). Meanwhile, the use of catalytically inactive PDE4 species in a so-called dominant negative approach provides proof of principal that disruption of specific interactions can give rise to functional effects (see Sect. 3.3).

0 0

Post a comment