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

doi:10.1002/advs.202201258

	A Small Molecule Selected from a DNA-Encoded Library of Natural Products That Binds to TNF-alpha and Attenuates Inflammation In Vivo
	Wang, Shuyue1,2,3,4 ; Shi, Xiaojie1 ; Li, Jie1 ; Huang, Qianping1,2,3,4 ; Ji, Qun1 ; Yao, Ying1,2,3,4 ; Wang, Tao1,2,3,4 ; Liu, Lili1 ; Ye, Min 5; Deng, Yun 6; Ma, Peixiang1,7 ; Xu, Hongtao1 ; Yang, Guang1
	2022-07-25
发表期刊	ADVANCED SCIENCE (IF:14.3[JCR-2023],16.3[5-Year])
EISSN	2198-3844
发表状态	已发表
DOI	10.1002/advs.202201258
摘要	Tumor necrosis factor alpha (TNF-alpha) inhibitors have shown great success in the treatment of autoimmune diseases. However, to date, approved drugs targeting TNF-alpha 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-alpha and the cognate receptor. Initially, to select molecules capable of binding to TNF-alpha, "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-alpha, but also lead to the blockage of TNF-alpha/TNFR1 interaction. Significantly, kaempferol attenuates the TNF-alpha 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-alpha and blocking its signal transduction, a promising starting point for the development of a small molecule TNF-alpha inhibitor for use in the clinical setting.
关键词	DNA-encoded library flavonoid inflammation kaempferol tumor necrosis factor alpha
URL	查看原文
收录类别	SCI ; EI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China[22177073,21502114,"U19A2011"] ; First-Class Discipline Development by Chengdu University of TCM[CZYJC1905] ; Key Research Project of Zhejiang Lab[2021PE0AC06] ; Ministry of Science and Technology of China[2021YFA1100800]
WOS研究方向	Chemistry ; Science & Technology - Other Topics ; Materials Science
WOS类目	Chemistry, Multidisciplinary ; Nanoscience & Nanotechnology ; Materials Science, Multidisciplinary
WOS记录号	WOS:000799703100001
出版者	WILEY
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/187887
专题	生命科学与技术学院_博士生免疫化学研究所_特聘教授组_功能筛选实验室免疫化学研究所_特聘教授组_抗体设计学实验室生命科学与技术学院_硕士生
通讯作者	Ma, Peixiang; Xu, Hongtao; Yang, Guang
作者单位	1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Inst Biochem & Cell Biol, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 5.Peking Univ, Sch Pharmaceut Sci, State Key Lab Nat & Biomimet Drugs, Beijing 100871, Peoples R China 6.Chengdu Univ Tradit Chinese Med, Sch Pharm, State Key Lab Southwestern Chinese Med Resources, Chengdu 611137, Sichuan, Peoples R China 7.Shanghai Jiao Tong Univ, Shanghai Peoples Hosp 9, Dept Orthoped Surg, Shanghai Key Lab Orthoped Implants,Sch Med, Shanghai 200011, Peoples R China
第一作者单位	免疫化学研究所; 生命科学与技术学院
通讯作者单位	免疫化学研究所
第一作者的第一单位	免疫化学研究所
推荐引用方式 GB/T 7714	Wang, Shuyue,Shi, Xiaojie,Li, Jie,et al. A Small Molecule Selected from a DNA-Encoded Library of Natural Products That Binds to TNF-alpha and Attenuates Inflammation In Vivo[J]. ADVANCED SCIENCE,2022.
APA	Wang, Shuyue.,Shi, Xiaojie.,Li, Jie.,Huang, Qianping.,Ji, Qun.,...&Yang, Guang.(2022).A Small Molecule Selected from a DNA-Encoded Library of Natural Products That Binds to TNF-alpha and Attenuates Inflammation In Vivo.ADVANCED SCIENCE.
MLA	Wang, Shuyue,et al."A Small Molecule Selected from a DNA-Encoded Library of Natural Products That Binds to TNF-alpha and Attenuates Inflammation In Vivo".ADVANCED SCIENCE (2022).