Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative
Background: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicin...
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doaj-e0f98ec649034702868cf36f10fef7402021-02-01T06:15:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122021-02-011110.3389/fphar.2020.624059624059Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone DerivativeMingqian Zhou0Yiqi Wang1Xiaoying Lin2Jieping Wan3Chengping Wen4College of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Pharmaceutical Science, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang, ChinaCollege of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, ChinaBackground: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicinally important molecules with diverse pharmacological activities, including anti-inflammatory activity. The present study focused on novel synthesized 3,4-dihydropyrimidinone derivatives and evaluated their inhibitory effects on TLR4.Methods: A series of 3,4-dihydropyrimidinone derivatives were recently synthesized and evaluated for their TLR4 inhibition activities and cytotoxic on HEK-BlueTM hTLR4 cells with the help of QUANTI-Blue assay and MTS assay. Selected compound 3 was analyzed for its molecular docking with TLR4 by using Autodock vina 1.1.2. Its effect on the TLR4 pathway related cytokines was also evaluated in THP-1 cells and human peripheral blood mononuclear cells by using real-time PCR, ELISA and western blot.Results: Five compounds were synthesized and characterized for effectiveness based on 3,4-dihydropyrimidinone. Compound 3 was found to be the potent hybrid among the synthesized compounds, with high TLR4 inhibition activities and low cytotoxic activities against HEK-BlueTM hTLR4 cells. Molecular docking analysis showed that two hydrogen bonds between compound 3 and residues Asp209(TLR4) and Asp99(MD-2) mainly contribute to the TLR4 inhibition. In addition, compound 3 suppressed LPS-induced of the mRNA expression of TLR4, IP-10, TNF-α, IL-6, IL-12A, and IL-12B, the protein expression of pIRF3 and pNFκB and the secretion of IP-10, TNF-α in THP-1 cell line. Compound 3 also inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β but increased IP-10 at mRNA levels in human peripheral blood mononuclear cells.Conclusion: Our study reveals compound 3, a novel 3,4-dihydropyrimidinone derivative, is a potential TLR4 antagonist, which opens up new research avenues for the development of promising therapeutic agents for inflammatory and autoimmune diseases.https://www.frontiersin.org/articles/10.3389/fphar.2020.624059/full34-dihydropyrimidinonesDHPMsTLR4antagonistinhibition |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Mingqian Zhou Yiqi Wang Xiaoying Lin Jieping Wan Chengping Wen |
spellingShingle |
Mingqian Zhou Yiqi Wang Xiaoying Lin Jieping Wan Chengping Wen Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative Frontiers in Pharmacology 3 4-dihydropyrimidinones DHPMs TLR4 antagonist inhibition |
author_facet |
Mingqian Zhou Yiqi Wang Xiaoying Lin Jieping Wan Chengping Wen |
author_sort |
Mingqian Zhou |
title |
Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative |
title_short |
Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative |
title_full |
Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative |
title_fullStr |
Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative |
title_full_unstemmed |
Specific TLR4 Blocking Effect of a Novel 3,4-Dihydropyrimidinone Derivative |
title_sort |
specific tlr4 blocking effect of a novel 3,4-dihydropyrimidinone derivative |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2021-02-01 |
description |
Background: Toll-like receptor 4 (TLR4) initiates both innate and adaptive immune responses, which plays an important protective role in self-defense mechanisms. Excessive or inappropriate TLR4 activation causes the development of many autoimmune diseases. Dihydropyrimidinone derivatives are medicinally important molecules with diverse pharmacological activities, including anti-inflammatory activity. The present study focused on novel synthesized 3,4-dihydropyrimidinone derivatives and evaluated their inhibitory effects on TLR4.Methods: A series of 3,4-dihydropyrimidinone derivatives were recently synthesized and evaluated for their TLR4 inhibition activities and cytotoxic on HEK-BlueTM hTLR4 cells with the help of QUANTI-Blue assay and MTS assay. Selected compound 3 was analyzed for its molecular docking with TLR4 by using Autodock vina 1.1.2. Its effect on the TLR4 pathway related cytokines was also evaluated in THP-1 cells and human peripheral blood mononuclear cells by using real-time PCR, ELISA and western blot.Results: Five compounds were synthesized and characterized for effectiveness based on 3,4-dihydropyrimidinone. Compound 3 was found to be the potent hybrid among the synthesized compounds, with high TLR4 inhibition activities and low cytotoxic activities against HEK-BlueTM hTLR4 cells. Molecular docking analysis showed that two hydrogen bonds between compound 3 and residues Asp209(TLR4) and Asp99(MD-2) mainly contribute to the TLR4 inhibition. In addition, compound 3 suppressed LPS-induced of the mRNA expression of TLR4, IP-10, TNF-α, IL-6, IL-12A, and IL-12B, the protein expression of pIRF3 and pNFκB and the secretion of IP-10, TNF-α in THP-1 cell line. Compound 3 also inhibited LPS-induced expression of TNF-α, IL-6, and IL-1β but increased IP-10 at mRNA levels in human peripheral blood mononuclear cells.Conclusion: Our study reveals compound 3, a novel 3,4-dihydropyrimidinone derivative, is a potential TLR4 antagonist, which opens up new research avenues for the development of promising therapeutic agents for inflammatory and autoimmune diseases. |
topic |
3 4-dihydropyrimidinones DHPMs TLR4 antagonist inhibition |
url |
https://www.frontiersin.org/articles/10.3389/fphar.2020.624059/full |
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