Catalytic Activity Alternation of an Artificial Metalloenzyme by Switchable Binding to the Proteins

Abstract An artificial metalloenzyme (ArM) utilizing a human serum albumin (HSA) scaffold exhibits remarkable catalytic stability due to the presence of a catalytic center within the deep hydrophobic pocket, demonstrating potential in vivo applicability for disease treatment via a prodrug activation strategy. Additionally, the development of latent catalysts is an important consideration for catalyst therapy to suppress the undesired activation of prodrugs. In this study, we developed a catalytic activity control system using a bispecific artificial metallopeptide, composed of a CpRu catalyst, an Fc‐binding peptide, and an albumin‐binding ligand. This metallopeptide individually interacted with both HSA and IgG, exhibiting catalytic activity change depending on the binding protein. The catalytic activity was enhanced when the metallopeptide was displaced from the pocket by interaction with IgG compared to the ArM formed with HSA, whereas no activity change was observed in the traditional ArM lacking the Fc‐binding peptide unit. This is the first report of the activity switching in an ArM by changing the binding place of the metal catalyst. We anticipated that this system could lead to further development of the concept for in vivo synthesis of drug molecules, termed “therapeutic in vivo synthetic chemistry” realizing the disease therapy without side effects of drugs.