Application of artificial backbone connectivity in the development of metalloenzyme mimics

Abstract

Metal-dependent enzymes are abundant and vital catalytic agents in nature. The functional versatility of metalloenzymes has made them common targets for improvement by protein engineering as well as mimicry by de novo designed sequences. In both strategies, the incorporation of non-canonical cofactors and/or non-canonical side chains has proved a useful tool. Less explored—but similarly powerful—is the utilization of non-canonical covalent modifications to the polypeptide backbone itself. Such efforts can entail either introduction of limited artificial monomers in natural chains to produce heterogeneous backbones or construction of completely abiotic oligomers that adopt defined folds. Herein, we review recent research applying artificial protein-like backbones in the construction of metalloenzyme mimics, highlighting progress as well as open questions in this emerging field.