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Production of next generation modulators of pannexins and connexins as novel therapeutics in the treatment of inflammatory cardiovascular, hepatic and joint diseases.

Periodic Reporting for period 1 - PANACHE (Production of next generation modulators of pannexins and connexins as novel therapeutics in the treatment of inflammatory cardiovascular, hepatic and joint diseases.)

Reporting period: 2020-03-01 to 2021-02-28

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 (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 (hemi)channel inhibitors. PANACHE therefore is a timely project, since it will generate a novel generation of (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 (hemi)channel inhibitors that can be used for the establishment of a generic approach to synergize current therapy of hard-to-treat inflammatory diseases. PANACHE will focus in particular on cardiovascular, liver and joint disease, all that have a high prevalence and impose a substantial financial burden in Europe. For this reason, PANACHE will have a deep and broad impact on society.

The project has 3 overall objectives:
- The production of Panx1, Cx43 and Cx32 (hemi)channel inhibitors.
- The in vitro and in silico testing of Panx1, Cx43 and Cx32 (hemi)channel inhibitors.
- The in vivo testing of Panx1, Cx43 and Cx32 (hemi)channel inhibitors for cardiovascular, liver and joint disease therapeutic purposes.
In the first reporting period, 100 potential inhibitors of Panx1 channels, Cx43 or Cx32 hemichannels have been synthetized using different approaches. At the same time, solid cell culture assays have been developed to test the effects of these newly synthetized compounds on the activity of Panx1 channels, Cx43 or Cx32 hemichannels. Several compounds have already been tested using these assays and showed to be promising inhibitors of Panx1 channels or Cx43 hemichannels. In parallel, computer-based models have been generated and successfully applied to predict physico-chemical properties of the newly synthetized compounds.
Selective and in vivo-applicable Panx1, Cx43 and Cx32 (hemi)channel inhibitors are currently not available. By applying innovative synthesis methods, such compounds will be produced for the very first time, which is a major step beyond the current state-of-the-art. These compounds will not only be cordially welcomed in basic research, namely to further investigate the role of Panx1, Cx43 and Cx32 (hemi)channels in cells and tissues, but will equally raise interest in the clinical and pharmaceutical area. In this respect, a market analysis performed in the first reporting period showed high market potential, especially for Panx1 channel inhibitors for the treatment of chronic liver disease. Since the activation of Panx1, Cx43 and Cx32 (hemi)channels has been associated with disease, in particular inflammation, they represent major therapeutic targets. The novel Panx1, Cx43 and Cx32 (hemi)channel inhibitors therefore seem promising new drugs. This is thoroughly investigated in PANACHE in a tiered approach consisting of in vitro, in silico and in vivo testing. For proof-of-concept purposes, focus is put on inflammatory diseases in the cardiovascular system, liver and joints, which are highly prevalent diseases. For this reason, PANACHE will have a deep and broad impact on society by alleviating health care costs, improving the quality of life of patients and even saving lives. By doing so, PANACHE will put Europe in an international pole position regarding the development of new anti-inflammatory drugs.
PANACHE consortium (kick-off meeting, Brussels-Belgium, 6 March 2020)