Description

Adding new chemistry to proteins and peptides is one of the most powerful ideas in synthetic biology. For example, swapping an amide bond for an ester or thioester can unlock new stability, reactivity, or function.

Nature already uses extended backbones. Many natural products contain β-, γ-, or δ-linkages instead of standard α-amino acid bonds. These include drugs and bioactive molecules like taxol, andrimid, actinoramide A, zorbamycin, and pyloricidin D.

Enter BEAR: Backbone Extension by Acyl Rearrangement. In this paper, the authors highlight edit the protein backbone after the protein is made! The researchers designed special hydroxy acids that carry a masked amine nucleophile on the side chain. After the protein is made, the hidden amine gets unmasked and triggers a spontaneous intramolecular rearrangement - altering the backbone after it's created.

Citation: Roe et al., 2025

Standard proteins use alpha-amino acid backbones exclusively, but many bioactive natural products (taxol, andrimid, actinoramide A) contain beta-, gamma-, or delta-linkages. Accessing these extended backbone architectures in ribosomally produced proteins has been difficult because the ribosome normally makes only alpha-peptide bonds.

BEAR (Backbone Extension by Acyl Rearrangement) addresses this through a post-translational trick. Hydroxy acid ncAAs carrying masked amine groups are incorporated normally by the ribosome. After translation, the amine is unmasked and triggers a spontaneous intramolecular rearrangement that extends the backbone, converting a standard alpha-linkage into a beta- or gamma-linkage within the finished protein (Roe et al., 2025).

This creates heteropolymer backbones, proteins containing mixed linkage types, using standard ribosomal translation followed by programmed chemistry. The implications extend to protease-resistant therapeutics, novel macrocyclic architectures, and materials with backbone properties that natural proteins may not achieve.

Source publication