Millicent Dockerill; Pramod M. Sabale; Francesco Russo; Sofia Barluenga; Nicolas Winssinger
JACS Au, 2024, 4(10), 4013–4022
https://doi.org/10.1021/jacsau.4c00738

Abstract

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.