Structure-based discovery of an immunomodulatory inhibitor of TLR1–TLR2 heterodimerization from a natural product-like database

Zhangfeng Zhong; Li Juan Liu; Zhi Qiang Dong; Lihua Lu; Modi Wang; Chung Hang Leung; Dik Lung Ma; Yitao Wang

doi:10.1039/c5cc02728d

Structure-based discovery of an immunomodulatory inhibitor of TLR1–TLR2 heterodimerization from a natural product-like database

Zhangfeng Zhong, Li Juan Liu, Zhi Qiang Dong, Lihua Lu, Modi Wang, Chung Hang Leung^*, Dik Lung Ma^*, Yitao Wang^*

^*Corresponding author for this work

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

51 Citations (Scopus)

Abstract

We report herein the identification of an immunomodulatory natural product-like compound 1 as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound 1 suppressed TNF-α and IL-6 secretion in Pam₃CSK₄-induced macrophages. Moreover, compound 1 inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-κB. Molecular docking revealed that compound 1 bound to the interface region of TLR1-TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound 1 has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date.

Original language	English
Pages (from-to)	11178-11181
Number of pages	4
Journal	Chemical Communications
Volume	51
Issue number	56
Early online date	21 May 2015
DOIs	https://doi.org/10.1039/c5cc02728d
Publication status	Published - 18 Jul 2015

Scopus Subject Areas

Catalysis
Electronic, Optical and Magnetic Materials
Ceramics and Composites
Chemistry(all)
Surfaces, Coatings and Films
Metals and Alloys
Materials Chemistry

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title = "Structure-based discovery of an immunomodulatory inhibitor of TLR1–TLR2 heterodimerization from a natural product-like database",

abstract = "We report herein the identification of an immunomodulatory natural product-like compound 1 as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound 1 suppressed TNF-α and IL-6 secretion in Pam3CSK4-induced macrophages. Moreover, compound 1 inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-κB. Molecular docking revealed that compound 1 bound to the interface region of TLR1-TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound 1 has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date.",

author = "Zhangfeng Zhong and Liu, {Li Juan} and Dong, {Zhi Qiang} and Lihua Lu and Modi Wang and Leung, {Chung Hang} and Ma, {Dik Lung} and Yitao Wang",

note = "Funding information: This work was supported by Hong Kong Baptist University (FRG2/13-14/008 and FRG2/14-15/004), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIRSCM, HKBU), the Health and Medical Research Fund (HMRF/ 13121482 and HMRF/14130522), the Research Grants Council (HKBU/201811, HKBU/204612, and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12), the Science and Technology Development Fund, Macao SAR (015/2011/A1 and 103/2012/A3) and the University of Macau (MYRG091(Y3-L2)-ICMS12-LCH, MYRG2015-00137-ICMS-QRCM and MRG023/LCH/2013/ICMS). Publisher copyright: {\textcopyright} The Royal Society of Chemistry 2015",

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doi = "10.1039/c5cc02728d",

language = "English",

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T1 - Structure-based discovery of an immunomodulatory inhibitor of TLR1–TLR2 heterodimerization from a natural product-like database

AU - Zhong, Zhangfeng

AU - Liu, Li Juan

AU - Dong, Zhi Qiang

AU - Lu, Lihua

AU - Wang, Modi

AU - Leung, Chung Hang

AU - Ma, Dik Lung

AU - Wang, Yitao

N1 - Funding information: This work was supported by Hong Kong Baptist University (FRG2/13-14/008 and FRG2/14-15/004), Centre for Cancer and Inflammation Research, School of Chinese Medicine (CCIRSCM, HKBU), the Health and Medical Research Fund (HMRF/ 13121482 and HMRF/14130522), the Research Grants Council (HKBU/201811, HKBU/204612, and HKBU/201913), the French National Research Agency/Research Grants Council Joint Research Scheme (A-HKBU201/12), the Science and Technology Development Fund, Macao SAR (015/2011/A1 and 103/2012/A3) and the University of Macau (MYRG091(Y3-L2)-ICMS12-LCH, MYRG2015-00137-ICMS-QRCM and MRG023/LCH/2013/ICMS). Publisher copyright: © The Royal Society of Chemistry 2015

PY - 2015/7/18

Y1 - 2015/7/18

N2 - We report herein the identification of an immunomodulatory natural product-like compound 1 as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound 1 suppressed TNF-α and IL-6 secretion in Pam3CSK4-induced macrophages. Moreover, compound 1 inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-κB. Molecular docking revealed that compound 1 bound to the interface region of TLR1-TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound 1 has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date.

AB - We report herein the identification of an immunomodulatory natural product-like compound 1 as a direct inhibitor of TLR1-TLR2 heterodimerization. Compound 1 suppressed TNF-α and IL-6 secretion in Pam3CSK4-induced macrophages. Moreover, compound 1 inhibited the phagocytic activity of macrophages, presumably through modulation of TLR1-TLR2 signaling and inactivation of NF-κB. Molecular docking revealed that compound 1 bound to the interface region of TLR1-TLR2 by forming two hydrogen bonds with residues lining the binding site. To our knowledge, compound 1 has been only the second inhibitor overall of TLR1-TLR2 heterodimerization reported to date.

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Structure-based discovery of an immunomodulatory inhibitor of TLR1–TLR2 heterodimerization from a natural product-like database

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