It is widely hypothesized that simple organic molecules that polymerized into peptides formed the foundation for early biochemical systems that led to the origins of life [1, 2, 3]. Recent advancements in metallopeptide design have shown that relatively small peptides, typically 40–50 amino acids in length, can spontaneously self-assemble into well-defined symmetric protein folds, capable of binding metal ions such as copper, iron, and zinc [4, 5, 6, 7]. These metallopeptides mimic the catalytic and structural functions of modern metalloenzymes, providing insights into potential evolutionary pathways. The capacity of short, self-assembling peptides to coordinate metal ions and perform catalysis suggests that similar primitive systems could have been early prototypes of natural enzymes [8,9].

This review focuses on advances made over the past four years in the design of metallopeptides as functional mimics of native metalloenzymes, seeking to replicate their efficiencies using simplified scaffolds differing significantly from their natural counterparts. The 2024 Nobel Prize in Chemistry emphasizes the influence of computational methods on enhancing protein design [10]. These methodologies are anticipated to accelerate the design of metallopeptides, broadening the potential for developing effective enzyme mimics and innovative catalytic systems.