MS4Drug · An Innovative Mass Spectrometry-Based Workflow for Drug Discovery
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-07-01 → 2021-06-30
- EU contribution
- €171,473
- Participants
- 1
- Scheme
- MSCA-IF-EF-SE
Lines connect the coordinator with its partners.
Results in brief
An Innovative Mass Spectrometry-Based Workflow for Drug Discovery
Preclinical phase of drug discovery is an early stage of research before testing in humans. This challenging process delivers key feasibility and safety data from in-vitro and laboratory animals disease models. Here, a central topic is the structural elucidation of the interaction between drug candidates and their protein targets. Several bioanalytical methods have been developed to address this question. Recently chemical cross-linking in combination with mass spectrometry (XLMS) demonstrated to be very powerful when added to the toolbox of those protein structural methods. The aim of this project was to introduce cross-linking mass spectrometry (XLMS) in the pipeline of drug discovery of a pharma company and integrate it with the preexisting approaches to study protein structure and dynamics. In fact, the combination of several techniques provides complementary and robust data. This project contributed to decipher the effect of drug candidates on the structure of several protein targets for different diseases and, more generally, to advance the XLMS approach into a routine method for drug discovery. This has been one of the first application of the XLMS approach in the field of structural biology in Italy.
Data: CORDIS, © European Union
Project 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.
Original text from CORDIS.
Participants
- CHIESI FARMACEUTICI SPA · ParmaCoordinatorItaly
Links
Data: CORDIS, © European Union