PhotoChemBio · Photoredox catalysis as a tool for the site-specific labelling of proteins

Photoredox catalysis as a tool for the site-specific labelling of proteins

The identification of disease-relevant protein targets that can be exploited for therapeutic benefit, broadly known as target ID, remains a fundamental goal of drug discovery. In recent years, the development of new biological and chemical techniques that accelerate target ID has become crucial amongst pharmaceutical research programmes. Despite significant advances, the identification of protein targets and their accompanying interaction networks remains a resource intensive, time-consuming, and often unsuccessful endeavour. While these methods remain state-of-the-art, the fundamental technology underpinning these approaches has evolved little in over 50 years. These traditional approaches to target ID rely on the activation of specific functional groups which are appended, via a chemical linker, to the drug of choice. Exposure to UV light allows these groups to decompose forming highly-reactive intermediates in close proximity to the protein of interest, which can rapidly insert into neighbouring chemical bonds, forming a formal 'covalent cross-link'. However, in the complex aqueous environment of a cell, near exclusive insertion into water occurs (>99%), and not the desired insertion into the target protein. Since the photoreactive group is directly appended to the small molecule ligand, unproductive quenching is far too frequently an insurmountable hurdle to successful target ID. As a result, the limitations in mechanistic understanding and subsequent off-target biological effects remains one of the leading causes of attrition for small-molecule drugs in the clinic. Therefore, the development of new methods to elucidate small molecule/protein interactions has the potential to increase significantly the success of medicinal target selections and ultimately reduce patient morbidity.

Data: CORDIS, © European Union