Evolution of chemistry and selection technology for DNA-encoded library.

DNA-encoded chemical library (DEL) links the power of amplifiable genetics and the non-self-replicating chemical phenotypes, generating a diverse chemical world. In analogy with the biological world, the DEL world can evolve by using a chemical central dogma, wherein DNA replicates using the PCR reactions to amplify the genetic codes, DNA sequencing transcripts the genetic information, and DNA-compatible synthesis translates into chemical phenotypes. Importantly, DNA-compatible synthesis is the key to expanding the DEL chemical space. Besides, the evolution-driven selection system pushes the chemicals to evolve under the selective pressure, i.e., desired selection strategies. In this perspective, we summarized recent advances in expanding DEL synthetic toolbox and panning strategies, which will shed light on the drug discovery harnessing in vitro evolution of chemicals via DEL.

A Small Molecule Selected from a DNA-Encoded Library of Natural Products That Binds to TNF-α and Attenuates Inflammation In Vivo.

Tumor necrosis factor α (TNF-α) inhibitors have shown great success in the treatment of autoimmune diseases. However, to date, approved drugs targeting TNF-α are restricted to biological macromolecules, largely due to the difficulties in using small molecules for pharmaceutical intervention of protein-protein interactions. Herein the power of a natural product-enriched DNA-encoded library (nDEL) is exploited to identify small molecules that interfere with the protein-protein interaction between TNF-α and the cognate receptor. Initially, to select molecules capable of binding to TNF-α , "late-stage" DNA modification method is applied to construct an nDEL library consisted of 400 sterically diverse natural products and pharmaceutically active chemicals. Several natural products, including kaempferol, identified not only show direct interaction with TNF-α, but also lead to the blockage of TNF-α/TNFR1 interaction. Significantly, kaempferol attenuates the TNF-α signaling in cells and reduces the 12-O-tetradecanoylphorbol-13-acetateinduced ear inflammation in mice. Structure-activity-relationship analyses demonstrate the importance of substitution groups at C-3, C-7, and C-4' of kaempferol. The nDEL hit, kaempferol, represents a novel chemical scaffold capable of specifically recognizing TNF-α and blocking its signal transduction, a promising starting point for the development of a small molecule TNF-α inhibitor for use in the clinical setting.