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Leveraging chemical proteomics

NCCR researchers of the “Chemical systems biology” project screen for small molecules that target various signalling and/or biosynthetic pathways in yeast and in higher eukaryotes. Highlight on its NCCR chemical proteomics lab activities.

Interview with Professor Alexander Adibekian, Principal Investigator

How are the methods and technologies used in your lab helping to answer questions raised within this project?

As a chemical proteomics lab, we are trying to contribute our part to the overall success of the NCCR, in particular by developing novel technologies to help other research groups with the global identification of protein targets of small molecules of their interest. These molecules for example include hits identified in phenotypic chemical genetics screens or compounds with intriguing biological properties that were synthesized in their lab.

By using the hypervalent iodide probe from Pr. Waser, you developed a new methodology for proteomics. What would you say are the main advantages of this new methodology over the one already in place (namely advantages of two step labelling, utility of having two probes). Will you continue to improve the methodology by adding more probes or look for one single probe with broader coverage?

This new methodology for proteomics allows detection and monitoring of up to ~3000 reactive cysteines in any given cellular proteome in one single experiment, thus providing a comprehensive proteome-wide picture of small molecule-cysteine interactions (Angew. Chem. Int. Ed. 2015, 54, 10852). This is achieved via strategic use of two clickable, cysteine-reactive chemical probes with complementary selectivity profiles, iodoacetamide alkyne and ethynyl benziodoxolone JW-RF-010. We have shown that JW-RF-010 alkynylates cysteines in complex proteomes fast, under mild physiological conditions, and with a very high degree of chemoselectivity. We have also demonstrated the utility of alkynyl benziodoxolones for chemical proteomics applications by identifying the proteomic targets of curcumin, a diarylheptanoid natural product that was and still is part of multiple human clinical trials as anticancer agent. Projecting forward, we would like to develop additional chemical scaffolds for cysteine-reactive probes that should, in principle, allow us to further expand the cysteinome coverage.

Did you face any experimental or intellectual roadblocks?

As any other research group, we as well occasionally face experimental roadblocks. There is no general recipe to avoid these roadblocks, but being in contact with such an excellent team of NCCR scientists coming from very different disciplines helps tremendously to overcome these obstacles.

What do you think is going to be the greatest impact or possible applications of the project for life sciences?

Small molecules identified in this project may become valuable research tools for biologists interested in studying specific signalling or biosynthetic in yeast or mammalian cells. Moreover, the identified compounds may also serve as basic blueprints for the development of new generations of drugs that target these specific pathways.

From 2013 to 2017, Alexander Adibekian wasTenure Track Assistant Professor in the Department of Organic Chemistry at the UNIGE. In 2017, he joined the Scripps Research Institute as Associate Professor. His research interests include the discovery of new cysteine-reactive small molecules and the identification of their proteomic targets, as well as the development of novel chemical strategies that allow rapid access to collections of structurally diverse cysteine-reactive small molecules.

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