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.