Descrizione del progetto
Sforzi per scoprire farmaci per l’ipertensione polmonare
L’ipertensione arteriosa polmonare è un raro disturbo associato a un’elevata pressione sanguigna nei vasi che riforniscono i polmoni. La maggior parte dei farmaci punta a contrastare la vasocostrizione indotta dal restringimento o dall’ostruzione che si verificano nelle piccole artiere presenti nei polmoni. Prove recenti indicano che gli inibitori volti a contrastare le protein-chinasi associate a Rho (ROCK, Rho-associated protein kinase) possono apportare benefici ai pazienti affetti da ipertensione arteriosa polmonare bersagliando la rimodellizzazione vascolare e l’infiammazione nei polmoni. L’obiettivo del progetto MS4Drug, finanziato dall’UE, è quello di caratterizzare i cambiamenti conformazionali nelle ROCK in vitro e nell’ambiente cellulare indotto da tali inibitori. Oltre ad approfondire i meccanismi molecolari alla base delle vie di segnalazione delle ROCK, i ricercatori si augurano di progettare farmaci migliorati per combattere l’ipertensione arteriosa polmonare.
Obiettivo
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.
Campo scientifico
- 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
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-SE - Society and Enterprise panelCoordinatore
43122 Parma
Italia