Unknown

Dataset Information

0

DNA-Encoded Library Hit Confirmation: Bridging the Gap Between On-DNA and Off-DNA Chemistry.


ABSTRACT: DNA-encoded library (DEL) technology is a powerful platform for hit identification in academia and the pharmaceutical industry. When conducting off-DNA resynthesis hit confirmation after affinity selection, PCR/sequencing, and data analysis, one typically assumes a "one-to-one" relationship between the DNA tag and the chemical structure of the attached small-molecule it encodes. Because library synthesis often yields a mixture, this approximation increases the risk of overlooking positive discoveries and valuable information. To address this issue, we apply a library synthesis "recipe" strategy for on-DNA resynthesis using a cleavable linker, followed by direct affinity selection mass spectrometry (AS-MS) evaluation and identification of binder(s) from the released small-molecule mixture. We validate and showcase this approach employing the receptor-interacting-protein kinase 2 (RIP2) DEL campaign. We also designed and developed two cleavable linkers to enable this method, a photocleavable linker (nitrophenyl-based) and acid-labile linker (tetrahydropyranyl ether). The strategy provides an effective means of hit identification and rapid determination of key active component(s) of the mixture.

SUBMITTER: Xia B 

PROVIDER: S-EPMC8274064 | biostudies-literature |

REPOSITORIES: biostudies-literature

Similar Datasets

| S-EPMC3565289 | biostudies-literature
| S-EPMC3041685 | biostudies-literature
| S-EPMC6957756 | biostudies-literature
| S-EPMC6786493 | biostudies-literature
| S-EPMC6723020 | biostudies-literature
| S-EPMC6545731 | biostudies-literature
| S-EPMC8456907 | biostudies-literature
| S-EPMC3752167 | biostudies-other
| S-EPMC4617782 | biostudies-literature
| S-EPMC6061867 | biostudies-literature