An Innovative Mass Spectrometry-Based Workflow for Drug Discovery

Projektinformationen

MS4Drug

ID Finanzhilfevereinbarung: 843585

DOI

10.3030/843585

Projekt abgeschlossen

EK-Unterschriftsdatum 30 April 2019

Startdatum 1 Juli 2019

Enddatum 30 Juni 2021

Finanziert unter

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Gesamtkosten

€ 171 473,28

EU-Beitrag

€ 171 473,28

Koordiniert durch

CHIESI FARMACEUTICI SPA
Italy

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

Berichtszeitraum: 2019-07-01 bis 2021-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

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.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

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.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

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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