Precisely Creating Enzyme-Mimetic Metal–Organic Framework for Unnatural Peptide Synthesis

Unnatural γ-amino acids and peptides have emerged as essential pharmacophores and versatile building blocks in drug molecules and biomaterials owing to their relatively flexible structures that enable unique interactions with specific biological targets. Despite their promising potential, nature lacks systematic biosynthetic approaches to structurally complex γ-amino acids and peptides, leaving a gap in the natural biosynthetic capabilities. Inspired by enzymatic catalysis and leveraging the advantages of metal-organic frameworks (MOFs), we designed a MOF-based catalytic system that incorporates both hydrogen-bond donors and organic photosensitizers within its pores, mirroring the catalytic pockets in biological systems. For the first time, this MOF system unlocks efficient amino acid homologation via hydrogen-bond/photoredox synergistic catalysis, permitting the modular synthesis of γ-amino acid derivatives. Practice of this homologation enables a programmable and divergent synthesis of γ-peptides. Mechanistic studies and density functional theory (DFT) calculations reveal key features, including multisite activation, induced fit, and synergistic catalysis, in this MOF system that closely resemble those found in natural enzymatic systems. Moreover, MOF catalysts exhibit superior catalytic performance with turnover numbers of up to 7800. Their high robustness is attributed to MOF's rigid framework, which maintains structural integrity under reaction conditions. This proof-of-concept research pushes the boundaries of both MOF catalysis and peptide synthesis, potentially inspiring the design of other synergistic catalysis.