Small molecules have always been of interest in chemistry and biology because of their ability to exert powerful effects on the functions of macromolecules that comprise living systems. This project work package focuses on the development and implementation of novel chemistries to access uncharted diversity space, develop novel screening methods and methodologies that can be applied to interrogate or manipulate biologically relevant systems.
A central theme of “Bioorthogonal chemistry” is to develop and implement innovative strategies in organic synthesis to expand small molecules structural/ functional diversity space beyond the commercially available space and to provide the required synthetic chemistry expertise to follow up on identified hits, identify inhibitors and perform medicinal chemistry follow-ups. Within that frame, a DNA-encoded chemical library (DECL) automated screening platform, complimentary to the high-throughput screening (HTS) platform ACCESS, has been developed and is in use.
Reactions that are suitable to modify proteins with chemical reporters have attracted significant attention over the past decades and this project aims to advance bioorthogonal reactions to tag cysteines or to report on biochemical process through luminescence and templated reactions, so as to provide a window into the function of these proteins through biophysical and mechanistic studies. Technological breakthroughs such as the expressed protein ligation have enabled the introduction of fluorophore, NMR probes and other reporters into complex proteins directly or permitted the targeting of a functionality in a chemoselective manner.
The scope and limitations of current technologies vary significantly in terms of bioorthogonality, compatibility with complex cellular environment, yield and selectivity. Indeed, compared to the situation with native purified proteins, the repertoire of chemical transformations is dramatically reduced in more complex settings such as lysates and even more in live cells. These techniques are well entrenched in ongoing projects: the labs of Adibekian and Winssinger reported the synthesis and cellular targets of deoxyelephantopins, a natural product with anticancer properties and the Gonzalez-Gaitan and Winssinger labs reported imaging of miRNA in live vertebrates (zebrafish). These examples illustrate the potential of existing methodologies but also represent clear opportunities that arise from broadening the scope of bioorthogonal reactions.