Research
The modulation of membrane-bound proteins by drugs is receiving increasing attention from both academia and industry. Among such proteins are pannexin1 (Panx1), connexin (Cx) 43 and Cx32 that form (hemi)channels at the plasma membrane surface. These (hemi)channels mediate cellular communication and have emerged as key players in inflammation. This carries translational relevance, as connexin and pannexin (hemi)channel inhibition could represent an innovative strategy for the treatment of a plethora of diseases. However, a hurdle in clinical exploration is the lack of appropriate connexin and pannexin (hemi)channel inhibitors. PANACHE therefore is a timely project, since it will generate a novel generation of connexin and pannexin (hemi)channel inhibitors as potential drugs. This will be accomplished by joining academic and industrial scientists from the chemical, chemo-informatics and biomedical fields as well as by relying on in vitro and in silico studies, animal experimentation and testing human material. PANACHE will allow taking a leap forward to the realization of its long-term vision, namely the production of metabolically robust and selective connexin and pannexin (hemi)channel inhibitors that can be used for the establishment of a generic approach to synergize current therapy of hard-to-treat inflammatory diseases.
Vision
The long-term vision of PANACHE is the production of an unprecedented set of connexin and pannexin (hemi)channel inhibitors that can be used for the establishment of a mechanistically-anchored and generic approach to synergize current therapy of hard-to-treat inflammatory diseases. For proof-of-concept purposes, focus will be put on inflammatory disorders in the cardiovascular system and liver. The scope of PANACHE is, however, much broader, as these innovative connexin and pannexin (hemi)channel inhibitors are anticipated to be equally applicable for the therapy of a number of other inflammatory disorders in which Panx1, Cx43 and Cx32 are known to be involved. Such applications will be tested in follow-up initiatives of PANACHE, thereby realizing its long-term vision.
Project objectives
The production of Panx1, Cx43 and Cx32 (hemi)channel inhibitors by the end of year 2.
The in vitro and in silico testing of Panx1, Cx43 and Cx32 (hemi)channel inhibitors by the end of year 2.
The in vivo testing of Panx1, Cx43 and Cx32 (hemi)channel inhibitors for cardiovascular and liver disease therapeutic purposes by the end of year 5.
Project structure
The PANACHE project started on 1 March 2020 and is set to run over a 60-months period. PANACHE is structured as 6 work packages (WP). WP1 will be devoted to management, dissemination, communication and exploitation of the project activities and results. WP2 will be aimed at the production of Panx1, Cx43 and Cx32 (hemi)channel inhibitors. In WP3, the produced Panx1, Cx43 and Cx32 (hemi)channel inhibitors will be tested in vitro for their efficacy and target selectivity. The Panx1, Cx43 and Cx32 (hemi)channel inhibitors will be simultaneously subjected to chemo-informatic and in silico modelling analysis for the prediction of physico-chemical, dynamic and kinetic features. The combined in vitro and in silico testing outcome will dictate the selection of number of Panx1, Cx43 and Cx32 (hemi)channel inhibitors for in vivo testing. The selected Panx1, Cx43 and Cx32 (hemi)channel inhibitors will be subsequently tested in parallel in human-relevant mouse models in WP4, WP5 and WP6 for their potential to counteract the clinical manifestation of a variety of acute and/or chronic inflammatory disorders in the cardiovascular system and liver either alone or in combination with anti-inflammatory drugs currently used.
