DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of bi...DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets,macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction(PPI)interface.We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold,which harvested binders against difficult targets such as tumor necrosis factor-α(TNF-α).Here,we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA,to explore larger chem-ical combinations on the same constant macrocyclic scaffold,following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns.We successfully integrated these or-thogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination.This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold,which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.展开更多
基金supported by the grants from the National Natu-ral Science Foundation of China(No.21907011)the Fundamental Research Funds for the Central Universities(Nos.2020CQJQY-Z002,2021CDJYGRH-002,China)+1 种基金the Natural Science Foundation of Chongqing(No.cstc2020jcyj-jqX0009,China)the China Post-doctoral Science Foundation(No.2020M683251).
文摘DNA-encoded chemical library(DEL)represents an emerging drug discovery technology to construct com-pound libraries with abundant chemical combinations.While drug-like small molecule DELs facilitate the discovery of binders against targets with defined pockets,macrocyclic DELs harboring extended scaffolds enable targeting of the protein–protein interaction(PPI)interface.We previously demonstrated the design of the first-generation DNA-encoded multiple display based on a constant macrocyclic scaffold,which harvested binders against difficult targets such as tumor necrosis factor-α(TNF-α).Here,we developed a novel strategy which utilized four orthogonal amine-protecting groups on DNA,to explore larger chem-ical combinations on the same constant macrocyclic scaffold,following the parallel paradigm to mimic the versatile antibody-like multivalent epitope recognition patterns.We successfully integrated these or-thogonal protecting groups with acylation and made a mock second-generation DNA-encoded display combination.This work illustrates a strategy to produce larger encoded multiple display on a constant macrocyclic scaffold,which could facilitate potential binder discovery with enhanced affinity to clinically significant PPI targets.
