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

Informazioni relative al progetto

PANACHE

ID dell’accordo di sovvenzione: 858014

DOI

10.3030/858014

Progetto chiuso

Data della firma CE 16 Dicembre 2019

Data di avvio 1 Marzo 2020

Data di completamento 28 Febbraio 2025

Finanziato da

• EXCELLENT SCIENCE - Future and Emerging Technologies (FET)

Costo totale

€ 3 503 628,75

Contributo UE

€ 3 503 628,75

Coordinato da

VRIJE UNIVERSITEIT BRUSSEL
Belgium

Periodic Reporting for period 3 - PANACHE (Production of next generation modulators of pannexins and connexins as novel therapeutics in the treatment of inflammatory cardiovascular and hepatic diseases.)

Periodo di rendicontazione: 2023-03-01 al 2025-02-28

Sintesi del contesto e degli obiettivi generali del progetto

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 represents 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 generates a novel type of (hemi)channel inhibitors as potential drugs. This is 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 as well as on animal experimentation. PANACHE allows 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 focuses in particular on cardiovascular and liver disease, all that have a high prevalence and impose a substantial financial burden in Europe. For this reason, PANACHE has 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 and liver disease therapeutic purposes.

At conclusion of the project, focus has been put on Panx1 channels as the most promising target. Peptidomimetic inhibitors of Panx1 channels have been successfully tested in mouse models of acute and chronic cardiovascular and liver inflammation.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

In the first reporting period, as much as 100 potential Panx1, Cx43 and Cx32 (hemi)channel inhibitors 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, Cx43 and Cx32 (hemi)channels. Several of these compounds showed to be promising inhibitors of Panx1, Cx43 or Cx32 (hemi)channels. In parallel, computer-based models have been generated and successfully applied to predict physico-chemical properties of the newly synthetized compounds.

In the second reporting period, more advanced inhibitors of Panx1 and Cx43 (hemi)channels have been produced. These compounds have been thoroughly tested in a diversity of cell culture models for their potential to inhibit Panx1 or Cx43 (hemi)channel activity and to counteract inflammation. The computational work was targeted towards producing quantitative structure-activity relationship models to predict properties such as solubility of the compounds as well as towards establishing molecular modelling models to predict binding of the compounds to their targets. Both the in vitro and the in silico testing has led to the selection of a limited number of optimized inhibitors of Panx1 and Cx43 (hemi)channels that will be tested in vivo in the third reporting period.

In the third reporting period, peptidomimetic inhibitors of Panx1 channels have been successfully tested in mouse models of acute and chronic cardiovascular and liver inflammation in combination with further in vitro testing and in silico modelling. The 2 key exploitable results of PANACHE are (i) new drug candidates for the treatment of inflammatory disorders, and (ii) software for the prediction of pharmacokinetics and structural characterization of peptides. A total of 18 manuscripts have been published and 3 workshops have been organized. Results have been presented orally or per poster on numerous (inter)national conferences. A website and relevant social media channels have been generated and maintained along with the publication of several newsletters and the production of a number of YouTube movies.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

The PANACHE impact is situated at 3 levels:

- The technological level: PANACHE has introduced a considerable disruptive innovation by generating peptidomimetics directed against difficult targets, in particular assembling and/or conformationally dynamic transmembrane proteins. A number of strategies have been used in this regard, including stabilization, macrocyclization and incorporation of unnatural conformationally constrained amino acids of known Panx1 or Cx43 (hemi)channel inhibitors, with main focus on Panx1 channels, as well as combinations of amino acid substitutions, global and local constraints. Impact at this level can be assessed by the number of publications, and presentations at conferences and workshops by the PANACHE consortium members.
- The societal level: PANACHE has introduced potentially new drug candidates for the treatment of hard-to-treat inflammatory cardiovascular and liver diseases, which not only will reduce health care costs, but first and foremost will increase the quality of life of millions of patients worldwide. Impact at this level can be assessed by the number of compounds that have been synthetized, subjected to in vitro testing and in silico modeling and successfully tested in vivo. Specifically, 3 compounds have been tested in mouse models of inflammatory cardiovascular disease, while 2 compounds have been assessed in mouse models of inflammatory liver diseases.
- The leadership level: PANACHE gathered a unique team with synergistic expertise, which has not only boosted (pharmaceutical) innovation, but that also has shaped the careers of the young investigators in the consortium.

PANACHE consortium (kick-off meeting, Brussels-Belgium, 6 March 2020)