Translation of Deoxyribonucleic Acid into Synthetic Alpha Helical Peptides for Darwinian Evolution.

DNA-encoded libraries connect the phenotypes of synthetic molecules to a DNA barcode; however, most libraries do not tap into the potential of Darwinian evolution. Herein, we report a DNA-templated synthesis (DTS) architecture to make peptides that are stabilized into α-helical conformations via head-to-tail supramolecular cyclization. Using a pilot library targeting MDM2, we show that repeated screening can amplify a binder from the lowest abundance in the library to a ranking that correlates to binding affinity. The study also highlights the need to design libraries such that the chemistry avoids biases from the heterogeneous yield in DTS.

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© 2024 The Authors. Published by American Chemical Society.

Déclaration de conflit d'intérêts

The authors declare no competing financial interest.