Description du sujet de thèse

Title: Synthesis of photoactivatable molecules for the spatiotemporal control of biological phenomena

The actin cytoskeleton controls cell shape and motility. Its dynamics are influenced by actin-binding proteins, regulating the polymerization of monomeric actin into filaments. Natural and synthetic small molecules are used by biologists to control this polymerization, and thus study the role of the actin cytoskeleton in various biological processes. In addition, advanced technologies involving photoactivatable compounds allow precise control in time and space of biological processes by light [1,2]. In this context, at the interface between synthetic chemistry and molecular biology, this project aims to develop a toolbox of photoactivatable chemical inhibitors targeting filament nucleation, elongation and branching, as well as their contractility by myosins, to decipher the complex relationships between dynamic remodeling of actin networks and cell migration. These molecules will be useful for biologists wishing to control cell movements.

The objective of the PhD project will be the development of a toolbox of photoactivatable molecules useful for the chemical biology of the actin cytoskeleton. The work will be carried out at the chemistry-biology interface in the fields of organic synthesis (Organic Synthesis Laboratory, Ecole Polytechnique, Palaiseau) and biochemistry and molecular biology (Institute of Integrative Cell Biology, University Paris-Saclay, Gif-sur-Yvette).

The methods used will involve the synthesis of small photoactivatable molecules, the characterization of their photochemical properties, their use to inhibit reconstituted biological processes in vitro observed by fluorescence microscopy and spectroscopy, and possibly applications on living cells.

Contexte de travail

The spatio-temporal controlof biological events with light within cells or tissues is a major challenge not only for the biological applications it offers (medicine, photopharmacology, nanobiotechnologies), but also for more fundamental applications aimed at studying and controlling essential and still poorly understood biological processes. Tools allowing such control [3,4] are therefore more necessary than ever in many fields and eagerly awaited by the community of biologists. This goal requires close collaboration between synthetic chemists and biologists. This work will be carried out between two laboratories, in organic synthesis and biochemistry/molecular biology, located in the Paris-Saclay sector.

References:
[1] (a) M. Skwarczynski et al. Bioorg. Med. Chem. Lett. 2006, 16, 4492-4496: Development of first photoresponsive prodrug of paclitaxel; (b) K. B. B. Buck and J. Q. Zheng, J. Neurosci. 2002, 22, 9358-9367: Growth Cone Turning Induced by Direct Local Modification of Microtubule Dynamics; (3) R. A. Gropeanu et al. PlosOne 2012, 7, e43657: Phototriggerable 29,7-Caged Paclitaxel.
[2] A. V. Karginov et al. J. Am. Chem. Soc. 2011, 133, 420-423: Light Regulation of Protein Dimerization and Kinase Activity in Living Cells Using Photocaged Rapamycin and Engineered FKBP.
[3] The Art of Building Small: from Molecular Switches to Motors, Ben Feringa, Nobel Prize Lecture 2016.
[4] M. Lerch et al. Angew. Chem. Int. Ed. 2016, 55, 2–24: Emerging Targets in Photopharmacology.

Contraintes et risques

The project will be carried out at the Organic Synthesis Laboratory (Palaiseau) and I2BC (Gif-sur-Yvette) according to the H&S rules used for organic synthesis work (under fumehoods in particular) and molecular biology/biochemistry. The student will benefit from all the equipment available in both laboratories.

Informations complémentaires

The applicant should have a Master in organic chemistry and/or bio-organic chemistry and/or chemical biology, and a strong and demonstrated interest for the biological interface and biology. Working in an international environment, he or she should be able to speak English.