Dockerill Millicent, Sabale Pramod M, Russo Francesco, Barluenga Sofia, Winssinger Nicolas
Department of Organic Chemistry, Faculty of Sciences, University of Geneva, Geneva 1211, Switzerland.
JACS Au. 2024 Oct 2;4(10):4013-4022. doi: 10.1021/jacsau.4c00738. eCollection 2024 Oct 28.
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.
DNA编码文库将合成分子的表型与DNA条形码联系起来；然而，大多数文库并未挖掘到达尔文进化的潜力。在此，我们报道了一种DNA模板合成（DTS）架构，用于制备通过头对尾超分子环化稳定为α-螺旋构象的肽。使用一个靶向MDM2的先导文库，我们表明重复筛选可以将文库中丰度最低的结合剂扩增到与结合亲和力相关的排名。该研究还强调了设计文库时需要考虑化学过程，以避免DTS中异质产率带来的偏差。
