Building Block Chemistry Makes Complex Unnatural Peptides Simply

Making molecules with tailored properties is a chemist’s forte, but some researchers are trying to spread the wealth. The latest idea for making synthesis a do-it-yourself endeavor for nonspecialists is inspired by nonribosomal peptide synthetase enzyme complexes (Nat. Chem. 2014, DOI: 10.1038/nchem.2048). In microbes, these enzymes make intricate peptidic molecules, such as the antibiotic vancomycin, by way of fermentation. Yi-Lin Huang and Jeffrey W. Bode of ETH Zurich set out to mimic this process with chemistry. Their “synthetic fermentation” is a ligation between an α-ketoacid initiator and isoxazolidine monomer. The reaction makes unnatural peptides by forging an amide bond between the building blocks. The product contains a new ketoacid so more monomers can be added. A terminator compound ends the elongation. The method works in water without organisms, enzymes, or coupling reagents. It proceeds in multiwell plates so that products can be screened for bioactivity without purification. As proof of concept, the duo synthesized a 6,000-compound library from 23 building blocks and identified an inhibitor of a hepatitis C protease. ETH Zurich has filed a patent application on the technology, and Bode hopes to make all of the building blocks commercially available.