An Innovative Mass Spectrometry-Based Workflow for Drug Discovery

Informazioni relative al progetto

MS4Drug

ID dell’accordo di sovvenzione: 843585

DOI

10.3030/843585

Progetto chiuso

Data della firma CE 30 Aprile 2019

Data di avvio 1 Luglio 2019

Data di completamento 30 Giugno 2021

Finanziato da

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Costo totale

€ 171 473,28

Contributo UE

€ 171 473,28

Coordinato da

CHIESI FARMACEUTICI SPA
Italy

Periodic Reporting for period 1 - MS4Drug (An Innovative Mass Spectrometry-Based Workflow for Drug Discovery)

Periodo di rendicontazione: 2019-07-01 al 2021-06-30

Sintesi del contesto e degli obiettivi generali del progetto

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.

Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti

We developed protocols of in-vitro cross-linking, footprinting and photo-covalent drug labeling which can be applied on a routine basis in drug discovery. Cross-linking and protein footprinting apply to the study of the 3D-structure of proteins and their conformational changes upon drug binding. Photo-covalent drugs can be obtained by derivatizing a drug candidate with a diazirine moiety and can be used to label the target protein and identify the drug binding site. We also gained a method to perform phosphoproteomic analysis which represents an asset to innovate analytical drug discovery workflow at Chiesi.

Those protocols have been applied and optimized on several enzyme and protein targets. The disclosure and publication of the details of those protocols and the results of our experiments will be delayed until patenting, following the Chiesi Intellectual Property procedures.

The fundamental principles of the structural proteomics methodologies applied along the project have been reviewed in Current Opinion in Biotechnology: Iacobucci C., Götze M., Sinz A. (2020). Cross-linking/mass spectrometry to get a closer view on protein interaction networks. Current opinion in biotechnology, 63, 48-53.

Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)

Integrating XLMS and other chemical proteomic methods in the pipeline of drug discovery may improve our understanding of the drug target interaction, speeding up the whole discovery process. Achieving this goal will have a positive impact on the marketing of novel molecules to treat diseases, and thus, on the life of patients.

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