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 (EuroSciVoc)
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
CORDIS classifies projects with EuroSciVoc, a multilingual taxonomy of fields of science, through a semi-automatic process based on NLP techniques. See: The European Science Vocabulary.
- medical and health sciences basic medicine pharmacology and pharmacy drug discovery
- medical and health sciences clinical medicine pneumology
- medical and health sciences basic medicine pharmacology and pharmacy pharmaceutical drugs
- natural sciences chemical sciences analytical chemistry mass spectrometry
- natural sciences biological sciences molecular biology structural biology
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Programme(s)
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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H2020-EU.1.3. - EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions
MAIN PROGRAMME
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H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility
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Topic(s)
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Calls for proposals are divided into topics. A topic defines a specific subject or area for which applicants can submit proposals. The description of a topic comprises its specific scope and the expected impact of the funded project.
Funding Scheme
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
Funding scheme (or “Type of Action”) inside a programme with common features. It specifies: the scope of what is funded; the reimbursement rate; specific evaluation criteria to qualify for funding; and the use of simplified forms of costs like lump sums.
MSCA-IF-EF-SE - Society and Enterprise panel
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Call for proposal
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
Procedure for inviting applicants to submit project proposals, with the aim of receiving EU funding.
(opens in new window) H2020-MSCA-IF-2018
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Net EU financial contribution. The sum of money that the participant receives, deducted by the EU contribution to its linked third party. It considers the distribution of the EU financial contribution between direct beneficiaries of the project and other types of participants, like third-party participants.
43122 Parma
Italy
The total costs incurred by this organisation to participate in the project, including direct and indirect costs. This amount is a subset of the overall project budget.