Translation of Deoxyribonucleic\nAcid into Synthetic\nAlpha Helical Peptides for Darwinian Evolution

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