An Innovative Mass Spectrometry-Based Workflow for Drug Discovery

Informations projet

MS4Drug

N° de convention de subvention: 843585

DOI

10.3030/843585

Projet clôturé

Date de signature de la CE 30 Avril 2019

Date de début 1 Juillet 2019

Date de fin 30 Juin 2021

Financé au titre de

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Coût total

€ 171 473,28

Contribution de l’UE

€ 171 473,28

Coordonné par

CHIESI FARMACEUTICI SPA
Italy

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

Période du rapport: 2019-07-01 au 2021-06-30

Résumé du contexte et des objectifs généraux du projet

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.

Travail effectué depuis le début du projet jusqu’à la fin de la période considérée dans le rapport et principaux résultats atteints jusqu’à présent

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.

Progrès au-delà de l’état des connaissances et impact potentiel prévu (y compris l’impact socio-économique et les conséquences sociétales plus larges du projet jusqu’à présent)

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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