Description du projet
Efforts de découverte de médicaments pour l’hypertension pulmonaire
L’hypertension artérielle pulmonaire (HTAP) est une maladie rare associée à une pression sanguine élevée dans les vaisseaux qui alimentent les poumons. La plupart des médicaments traitent la vasoconstriction induite par le rétrécissement ou l’obstruction des petites artères pulmonaires. Des données récentes indiquent que les inhibiteurs de la Rho kinase (ROCK) pourraient être bénéfiques aux patients atteints de HTAP en ciblant le remodelage vasculaire et l’inflammation dans les poumons. Le projet MS4Drug, financé par l’UE, a pour but de caractériser les changements de conformation des ROCK et dans l’environnement cellulaire induits par ces inhibiteurs. Parallèlement à l’étude des mécanismes moléculaires qui sous-tendent les voies de signalisation des ROCK, les chercheurs espèrent concevoir de meilleurs médicaments pour l’HTAP.
Objectif
Pulmonary Arterial Hypertension (PAH) is a life-threatening condition; even if treated, patients only have a 5-year survival rate of less than 60%. For the treatment of PAH, Chiesi Pharmaceuticals develops Rho-associated, coiled-coil-containing protein kinase (ROCK) inhibitors.
The aim of this project is to elucidate conformational changes in ROCK in vitro as well as in the cellular environment that are induced by anti-PAH drug candidates, which are currently being tested in preclinical trials at Chiesi Pharmaceuticals. The ROCK interactome will be mapped to gain detailed insights into the molecular mechanisms underlying the signaling pathways of ROCK. We will decipher the effect of anti-PAH drug candidates on the ROCK interactome and elucidate drug-induced conformational changes in ROCK. Identifying novel pharmacological targets modulating specific ROCK/protein interactions will eventually lead to novel drugs for an improved treatment of PAH.
This project will integrate, for the first time, in cell cross-lining mass spectrometry (XLMS), in conjunction with hydrogen/deuterium exchange mass spectrometry (HDX-MS), in the drug discovery pipeline of a pharma company. It will be the first application of the XLMS approach in the field of structural biology in Italy. The conformations and interactions of ROCK, derived by in cell XLMS, will allow a systematic validation of in vitro biochemical studies. This project aims to advance the in cell XLMS approach into a routine method for drug discovery on the system-wide level that complements HDX-MS studies using isolated proteins. Novel cross-linking reagent will be developed to bring the XLMS approach to a new level of time-resolved protein interaction studies. As such, the integrated approach described herein opens unmatched and novel perspectives for biotechnological and pharmaceutical companies.
The outcome of this project is expected to have a large impact on structural biology and drug discovery in general.
Champ scientifique
- medical and health sciencesbasic medicinepharmacology and pharmacydrug discovery
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugs
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteins
- natural scienceschemical sciencesanalytical chemistrymass spectrometry
- natural sciencesbiological sciencesmolecular biologystructural biology
Programme(s)
Régime de financement
MSCA-IF-EF-SE - Society and Enterprise panelCoordinateur
43122 Parma
Italie