Project description
Drug discovery efforts for pulmonary hypertension
Pulmonary arterial hypertension (PAH) is a rare disorder associated with high blood pressure in the vessels that supply the lungs. Most drugs address the induced vasoconstriction caused by the narrowing or obstruction in the small arteries in the lung. Recent evidence indicates that inhibitors against Rho-associated protein kinases (ROCKs) may benefit PAH patients by targeting vascular remodelling and inflammation in the lungs. The scope of the EU-funded MS4Drug project is to characterise the conformational changes in ROCKs in vitro as well as in the cellular environment induced by such inhibitors. Alongside investigation into the molecular mechanisms underlying the signalling pathways of ROCKs, researchers hope to design improved drugs for PAH.
Objective
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.
Fields of science
- 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)
Funding Scheme
MSCA-IF-EF-SE - Society and Enterprise panelCoordinator
43122 Parma
Italy