Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2
Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which...
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| Format: | Article |
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Frontiers Media S.A.
2022-02-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.835081/full |
| _version_ | 1819279441456529408 |
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| author | Siru Wu Siru Wu Cong Lin Tianshu Zhang Tianshu Zhang Bo Zhang Bo Zhang Yushan Jin Hongshuang Wang Hongyuan Li Yibo Wang Xiaohui Wang Xiaohui Wang Xiaohui Wang |
| author_facet | Siru Wu Siru Wu Cong Lin Tianshu Zhang Tianshu Zhang Bo Zhang Bo Zhang Yushan Jin Hongshuang Wang Hongyuan Li Yibo Wang Xiaohui Wang Xiaohui Wang Xiaohui Wang |
| author_sort | Siru Wu |
| collection | DOAJ |
| description | Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which may bring a cytokine storm in the body and cause severe sepsis. Existing molecules specialized in sepsis therapy are either in clinical trials or show mediocre effects. In this study, pentamidine, an approved drug used in the treatment of trypanosomiasis, was identified as a TLR4 antagonist. Saturation transferred difference (STD)-NMR spectra indicated that pentamidine directly interacted with TLR4’s co-receptor myeloid differentiation protein 2 (MD2) in vitro. Cellular thermal shift assay (CETSA) showed that pentamidine binding decreased MD2 stability, which was supported by in silico simulations that pentamidine binding rendered most regions of MD2 more flexible. Pentamidine was found to inhibit the formation of the TLR4/MD2/MyD88 complex and the activation of the TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream of the pro-inflammatory factors NO, TNF-α, and IL-1β. The bioisosteric replacement of the methylene group at the center 13′ site of pentamidine by the ether oxygen group significantly decreased its interactions with MD2 and abolished its TLR4 antagonist activity. Furthermore, pentamidine enhanced the survival rate of septic mice and exerted an anti-inflammatory effect on organs. All these data provide strong evidence that pentamidine may be an effective drug in alleviating inflammation and sepsis. |
| first_indexed | 2024-12-24T00:27:57Z |
| format | Article |
| id | doaj.art-1197cec91f544cf28e0ae8fc9090c65e |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-24T00:27:57Z |
| publishDate | 2022-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-1197cec91f544cf28e0ae8fc9090c65e2022-12-21T17:24:21ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-02-011310.3389/fphar.2022.835081835081Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2Siru Wu0Siru Wu1Cong Lin2Tianshu Zhang3Tianshu Zhang4Bo Zhang5Bo Zhang6Yushan Jin7Hongshuang Wang8Hongyuan Li9Yibo Wang10Xiaohui Wang11Xiaohui Wang12Xiaohui Wang13Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaDepartment of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaDepartment of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaDepartment of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, ChinaDepartment of Immunology and Department of Cell & Systems Biology, University of Toronto, Toronto, ON, CanadaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaLaboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, ChinaDepartment of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei, ChinaBeijing National Laboratory for Molecular Sciences, Beijing, ChinaToll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which may bring a cytokine storm in the body and cause severe sepsis. Existing molecules specialized in sepsis therapy are either in clinical trials or show mediocre effects. In this study, pentamidine, an approved drug used in the treatment of trypanosomiasis, was identified as a TLR4 antagonist. Saturation transferred difference (STD)-NMR spectra indicated that pentamidine directly interacted with TLR4’s co-receptor myeloid differentiation protein 2 (MD2) in vitro. Cellular thermal shift assay (CETSA) showed that pentamidine binding decreased MD2 stability, which was supported by in silico simulations that pentamidine binding rendered most regions of MD2 more flexible. Pentamidine was found to inhibit the formation of the TLR4/MD2/MyD88 complex and the activation of the TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream of the pro-inflammatory factors NO, TNF-α, and IL-1β. The bioisosteric replacement of the methylene group at the center 13′ site of pentamidine by the ether oxygen group significantly decreased its interactions with MD2 and abolished its TLR4 antagonist activity. Furthermore, pentamidine enhanced the survival rate of septic mice and exerted an anti-inflammatory effect on organs. All these data provide strong evidence that pentamidine may be an effective drug in alleviating inflammation and sepsis.https://www.frontiersin.org/articles/10.3389/fphar.2022.835081/fullToll-like receptor 4myeloid differentiation protein 2pentamidineinflammationsepsis |
| spellingShingle | Siru Wu Siru Wu Cong Lin Tianshu Zhang Tianshu Zhang Bo Zhang Bo Zhang Yushan Jin Hongshuang Wang Hongyuan Li Yibo Wang Xiaohui Wang Xiaohui Wang Xiaohui Wang Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 Frontiers in Pharmacology Toll-like receptor 4 myeloid differentiation protein 2 pentamidine inflammation sepsis |
| title | Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 |
| title_full | Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 |
| title_fullStr | Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 |
| title_full_unstemmed | Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 |
| title_short | Pentamidine Alleviates Inflammation and Lipopolysaccharide-Induced Sepsis by Inhibiting TLR4 Activation via Targeting MD2 |
| title_sort | pentamidine alleviates inflammation and lipopolysaccharide induced sepsis by inhibiting tlr4 activation via targeting md2 |
| topic | Toll-like receptor 4 myeloid differentiation protein 2 pentamidine inflammation sepsis |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.835081/full |
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