Functionalised Cofactor Mimics for Interactome Discovery and Beyond

Cofactors are required for almost half of all enzyme reactions, but their functions and binding partners are not fully understood even after decades of research. Functionalised cofactor mimics that bind in place of the unmodified cofactor can provide answers, as well as expand the scope of cofactor activity. Through chemical proteomics approaches such as activity‐based protein profiling, the interactome and localisation of the native cofactor in its physiological environment can be deciphered and previously uncharacterised proteins annotated. Furthermore, cofactors that supply functional groups to substrate biomolecules can be hijacked by mimics to site‐specifically label targets and unravel the complex biology of post‐translational protein modification. The diverse activity of cofactors has inspired the design of mimics for use as inhibitors, antibiotic therapeutics, and chemo‐ and biosensors, and cofactor conjugates have enabled the generation of novel enzymes and artificial DNAzymes. Cofactors are essential, but their functions and binding partners are not fully understood even after decades of research. Functionalised cofactor mimics that bind in place of the unmodified cofactor can provide answers, as well as expand the scope of cofactor activity. This Review outlines the growing use of cofactor mimics in interactome discovery, drug development, the study of post‐translational modifications, and other novel biotechnologies.