Open AccessA Small Molecule Selected from a DNA‐Encoded Library of Natural Products That Binds to TNF‐ α and Attenuates Inflammation In Vivo
Author(s) -
Wang Shuyue,
Shi Xiaojie,
Li Jie,
Huang Qianping,
Ji Qun,
Yao Ying,
Wang Tao,
Liu Lili,
Ye Min,
Deng Yun,
Ma Peixiang,
Xu Hongtao,
Yang Guang
Publication year - 2022
Publication title -
advanced science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.388
H-Index - 100
ISSN - 2198-3844
DOI - 10.1002/advs.202201258
Subject(s) - tumor necrosis factor alpha , kaempferol , small molecule , chemistry , in vivo , inflammation , natural product , dna , receptor , biochemistry , pharmacology , microbiology and biotechnology , biology , immunology , flavonoid , genetics , antioxidant
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 ( n DEL) 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 n DEL 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 n DEL 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.