Unlocking the therapeutic potential of artificial metalloenzymes

Abstract

In order to harness the functionality of metals, nature has evolved over billions of years to utilize metalloproteins as key components in numerous cellular processes. Despite this, transition metals such as ruthenium, palladium, iridium, and gold are largely absent from naturally occurring metalloproteins, likely due to their scarcity as precious metals. To mimic the evolutionary process of nature, the field of artificial metalloenzymes (ArMs) was born as a way to benefit from the unique chemoselectivity and orthogonality of transition metals in a biological setting. In its current state, numerous examples have successfully incorporated transition metals into a variety of protein scaffolds. Using these ArMs, many examples of new-to-nature reactions have been carried out, some of which have shown substantial biocompatibility. Given the rapid rate at which this field is growing, this review aims to highlight some important studies that have begun to take the next step within this field; namely the development of ArM-centered drug therapies or biotechnological tools.

Dual-Bioorthogonal Catalysis by a Palladium Peptide Complex

“…Proteins have been used as biocompatible supports for metals, mimicking the active site of metalloenzymes and forming artificial metalloenzymes (ArMs) . However, there are few examples of ArMs as bioorthogonal, homogeneous, TMC in living systems, due to their prohibitive macromolecular size. − Reducing the protein structure to small peptides could overcome large structure limitations, which include delivery issues, in situ metal–protein assembly, and immunogenicity. , …”

“…45−47 Reducing the protein structure to small peptides could overcome large structure limitations, which include delivery issues, in situ metal−protein assembly, and immunogenicity. 47,48 Metallopeptides are an exciting and highly appealing new type of bioorthogonal TMC, achieving homogeneous catalysis with minimal metal toxicity. 49,50 Here, we have synthesized a novel, bioorthogonal, homogeneous palladium peptide catalyst, consisting of a methyl salicylate tagged hydrophilic peptide (LLEYLKR) complexed to palladium.…”

Artificial Metalloproteins: At the Interface between Biology and Chemistry

“…The advancement of synthetic methodologies and biochemical tools such as protein engineering has recently reinvigorated the study of artificial metalloproteins (ArMs). This hybrid approach at the interface of chemical biology and synthetic chemistry aims to prepare new systems that address problems in a wide range of applications, including biocatalysis, 3 biotechnology, 4,5 protein structure and assembly, 6,7 and model chemistry. 8 Artificial metalloproteins are constructed by the introduction of non-native metallocofactors into a naturally occurring protein or through the design of de novo protein matrices, as summarized in Figure 1.…”

Exploring and Adapting the Molecular Selectivity of Artificial Metalloenzymes

“…While artificial enzymes have increasingly expanded to scaffolds composed of nanomaterials, DNA, and others, [1][2][3] the area of artificial metalloenzymes (ArM) addressed in this review is mainly focused on proteins that have been restructured or recomposed to catalyze reactions not previously observed for the native protein ( Figure 1). [4][5][6][7][8][9][10][11][12][13] Within the last few decades, rapid advancements in organometallic chemistry and protein engineering techniques have spearheaded efforts within the field to focus on introducing new-to-nature reactions that are compatible with living systems. In general, this has been achieved either through expanding the catalytic repertoire of existing metalloproteins, or through repurposing protein scaffolds with abiotic transition metals.…”