Citation: ZHANG Xiaozheng, ZHANG Tianshu, CUI Fengchao, LI Yunqi, PENG Yinghua, WANG Xiaohui. Toll-like Receptor 4 Small Molecule Modulators[J]. Chinese Journal of Applied Chemistry, ;2016, 33(8): 876-886. doi: 10.11944/j.issn.1000-0518.2016.08.160206 shu

Toll-like Receptor 4 Small Molecule Modulators

1.
a Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China;
2.
b University of Chinese Academy of Sciences, Beijing 100039, China;
3.
c State Key Laboratory of New Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China;
4.
d Key Laboratory of Synthetic Rubber, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China;
5.
e Key Laboratory of Special Animal Molecular Biology of Jilin Province, Specialty Research Institute of Chinese Academy of Agricultural Sciences, Changchun 130022, China

Corresponding author: WANG Xiaohui,
Received Date: 18 May 2016
Available Online: 6 June 2016
Fund Project:

Toll-like receptors(TLRs) are evolutionarily conserved innate immunity receptor proteins that detect pathogen-associated molecular patterns(PAMPs), danger-associated molecular patterns(DAMPs) and xenobiotic-associated molecular patterns(XAMPs), triggering inflammatory responses. TLR4 is the main receptor for bacterial lipopolysaccharide(LPS) and the accessory protein myeloid differentiation factor 2(MD-2) is responsible for ligand recognition. LPS binding induces(TLR4-MD-2-LPS)2 and TLR4/MD-2 complex dimeriztion, which activates TLR4 signaling and produce pro-inflammatory factors. The dysregulation of innate immune TLR4 signaling contributes to numerous pathological diseases. Therefore, TLR4/MD-2 is emerging as an important drug discovery target. In this review, we summarize the up-to-date discovery of TLR4 small molecule modulators and provide insights into future drug discovery, which will be interesting to colleagues major in chemical biology, medicinal chemistry, signal transduction and translational medicine.
- Toll-like receptor 4,
- myeloid differentiation factor 2,
- drug discovery,
- agonist,
- antagonist,
- innate immune
1. [1]
  [1] Takeuchi O,Akira S. Pattern Recognition Receptors and Inflammation[J]. Cell,2010,140(6):805-820.
2. [2]
  [2] Bachtell R,Hutchinson M R,Wang X H,et al. Targeting the Toll of Drug Abuse:The Translational Potential of Toll-like Receptor 4[J]. CNS Neurol Disord Drug Targets,2015,14(6):692-699.
3. [3]
  [3] Medzhitov R,Preston-Hurlburt P,Janeway C A,Jr. A Human Homologue of the Drosophila Toll Protein Signals Activation of Adaptive Immunity[J]. Nature,1997,388(6640):394-397.
4. [4]
  [4] Jin M S,Kim S E,Heo J Y,et al. Crystal Structure of the TLR1-TLR2 Heterodimer Induced by Binding of a Tri-acylated Lipopeptide[J]. Cell,2007,130(6):1071-1082.
5. [5]
  [5] Liu L,Botos I,Wang Y,et al. Structural Basis of Toll-like Receptor 3 Signaling with Double-stranded RNA[J]. Science,2008,320(5874):379-381.
6. [6]
  [6] Kim H M,Park B S,Kim J I,et al. Crystal Structure of the TLR4-MD-2 Complex with Bound Endotoxin Antagonist Eritoran[J]. Cell,2007,130(5):906-917.
7. [7]
  [7] Park B S,Song D H,Kim H M,et al. The Structural Basis of Lipopolysaccharide Recognition by the TLR4-MD-2 Complex[J]. Nature,2009,458(7242):1191-1195.
8. [8]
  [8] Yoon S I,Kurnasov O,Natarajan V,et al. Structural Basis of TLR5-Flagellin Recognition and Signaling[J]. Science,2012,335(6070):859-864.
9. [9]
  [9] Kang J Y,Nan X,Jin M S,et al. Recognition of Lipopeptide Patterns by Toll-like Receptor 2-Toll-like Receptor 6 Heterodimer[J]. Immunity,2009,31(6):873-884.
10. [10]
  [10] Tanji H,Ohto U,Shibata T,et al. Structural Reorganization of the Toll-like Receptor 8 Dimer Induced by Agonistic Ligands[J]. Science,2013,339(6126):1426-1429.
11. [11]
  [11] Tanji H,Ohto U,Shibata T,et al. Toll-like Receptor 8 Senses Degradation Products of Single-stranded RNA[J]. Nat Struct Mol Biol,2015,22(2):109-115.
12. [12]
  [12] Ohto U,Shibata T,Tanji H,et al. Structural Basis of CpG and Inhibitory DNA Recognition by Toll-like Receptor 9[J]. Nature,2015,520(7549):702-705.
13. [13]
  [13] Song W,Wang J,Han Z,et al. Structural Basis for Specific Recognition of Single-stranded RNA by Toll-like Receptor 13[J]. Nat Struct Mol Biol,2015,22(10):782-787.
14. [14]
  [14] Wang J,Chai J,Wang H. Structure of the Mouse Toll-like Receptor 13 Ectodomain in Complex with a Conserved Sequence from Bacterial 23S Ribosomal RNA[J]. FEBS J,2016,283(9):1631-1635.
15. [15]
  [15] Buchanan M M,Hutchinson M,Watkins L R,et al. Toll-like Receptor 4 in CNS Pathologies[J]. J Neurochem,2010,114(1):13-27.
16. [16]
  [16] Li J,Wang X H,Zhang F C,et al. Toll-like Receptors as Therapeutic Targets for Autoimmune Connective Tissue Diseases[J]. Pharmacol Ther,2013,138(3):441-451.
17. [17]
  [17] He W G,Liu Q Y,Wang L,et al. TLR4 Signaling Promotes Immune Escape of Human Lung Cancer Cells by Inducing Immunosuppressive Cytokines and Apoptosis Resistance[J]. Mol Immunol,2007,44(11):2850-2859.
18. [18]
  [18] Szajnik M,Szczepanski M J,Czystowska M,et al. TLR4 Signaling Induced by Lipopolysaccharide or Paclitaxel Regulates Tumor Survival and Chemoresistance in Ovarian Cancer[J]. Oncogene,2009,28(49):4353-4363.
19. [19]
  [19] Zeuke S,Ulmer A J,Kusumoto S,et al. TLR4-mediated Inflammatory Activation of Human Coronary Artery Endothelial Cells by LPS[J]. Cardiovasc Res,2002,56(1):126-134.
20. [20]
  [20] Wang X,Smith C,Yin H. Targeting Toll-like Receptors with Small Molecule Agents[J]. Chem Soc Rev,2013,42(12):4859-4866.
21. [21]
  [21] Kang S,Lee S P,Kim K E,et al. Toll-like Receptor 4 in Lymphatic Endothelial Cells Contributes to LPS-induced Lymphangiogenesis by Chemotactic Recruitment of Macrophages[J]. Blood,2009,113(11):2605-2613.
22. [22]
  [22] Poltorak A,He X L,Smirnova I,et al. Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in Tlr4 Gene[J]. Science,1998,282(5396):2085-2088.
23. [23]
  [23] Takeda K,Akira S. TLR Signaling Pathways[J]. Semin Immunol,2004,16(1):3-9.
24. [24]
  [24] Wang J,Hu Y,Deng W W,et al. Negative Regulation of Toll-like Receptor Signaling Pathway[J]. Microbes Infect,2009,11(3):321-327.
25. [25]
  [25] Shimazu R,Akashi S,Ogata H,et al. MD-2, a Molecule That Confers Lipopolysaccharide Responsiveness on Toll-like Receptor 4[J]. J Exp Med,1999,189(11):1777-1782.
26. [26]
  [26] Viriyakosol S,Tobias P S,Kitchens R L,et al. MD-2 Binds to Bacterial Lipopolysaccharide[J]. J Biol Chem,2001,276(41):38044-38051.
27. [27]
  [27] Nishitania C,Mitsuzawa H,Hyakushima N,et al. The Toll-like Receptor 4 Region Glu(24)-Pro(34) is Critical for Interaction with MD-2[J]. Biochem Biophys Res Commun,2005,328(2):586-590.
28. [28]
  [28] Resman N,Vasl J,Oblak A,et al. Essential Roles of Hydrophobic Residues in Both MD-2 and Toll-like Receptor 4 in Activation by Endotoxin[J]. J Biol Chem,2009,284(22):15052-15060.
29. [29]
  [29] Ohto U,Fukase K,Miyake K,et al. Structural Basis of Species-Specific Endotoxin Sensing by Innate Immune Receptor TLR4/MD-2[J]. Proc Natl Acad Sci USA,2012,109(19):7421-7426.
30. [30]
  [30] Wang Y,Su L,Morin M D,et al. TLR4/MD-2 Activation by a Synthetic Agonist with no Similarity to LPS[J]. Proc Nat Acad Sci,2016,113(7):E884-E893.
31. [31]
  [31] Stover A G,Da Silva Correia J,Evans J T,et al. Structure-activity Relationship of Synthetic Toll-like Receptor 4 Agonists[J]. J Biol Chem,2004,279(6):4440-4449.
32. [32]
  [32] Dunn-Siegrist I,Tissieres P,Drifte G,et al. Toll-like Receptor Activation of Human Cells by Synthetic Triacylated Lipid A-Like Molecules[J]. J Biol Chem,2012,287(20):16121-16131.
33. [33]
  [33] Peri F,Calabrese V. Toll-like Receptor 4(TLR4) Modulation by Synthetic and Natural Compounds:An Update[J]. J Med Chem,2014,57(9):3612-3622.
34. [34]
  [34] Pantel A,Cheong C,Dandamudi D,et al. A New Synthetic TLR4 Agonist, GLA, Allows Dendritic Cells Targeted with Antigen to Elicit Th1 T-cell Immunity in Vivo[J]. Eur J Immunol,2012,42(1):101-109.
35. [35]
  [35] Orr M T,Duthie M S,Windish H P,et al. MyD88 and TRIF Synergistic Interaction is Required for TH1-cell Polarization with a Synthetic TLR4 Agonist Adjuvant[J]. Eur J Immunol,2013,43(9):2398-2408.
36. [36]
  [36] Mata-Haro V,Cekic C,Martin M,et al. The Vaccine Adjuvant Monophosphoryl Lipid A as a TRIF-biased Agonist of TLR4[J]. Science,2007,316(5831):1628-1632.
37. [37]
  [37] Bowen W S,Minns L A,Johnson D A,et al. Selective TRIF-dependent Signaling by a Synthetic Toll-like Receptor 4 Agonist[J]. Sci Signal,2012,5(211):958-962.
38. [38]
  [38] Mancek-Keber M,Jerala R. Postulates for Validating TLR4 Agonists[J]. Eur J Immunol,2015,45(2):356-370.
39. [39]
  [39] Kawasaki K,Gomi K,Nishijima M. Cutting Edge: Gln22 of Mouse MD-2 is Essential for Species-Specific Lipopolysaccharide Mimetic Action of Taxol[J]. J Immunol,2001,166(1):11-14.
40. [40]
  [40] Kawasaki K,Nogawa H,Nishijima M. Identification of Mouse MD-2 Residues Important for Forming the Cell Surface TLR4-MD-2 Complex Recognized by Anti-TLR4-MD-2 Antibodies, and for Conferring LPS and Taxol Responsiveness on Mouse TLR4 by Alanine-Scanning Mutagenesis[J]. J Immunol,2003,170(1):413-420.
41. [41]
  [41] Resman N,Gradisar H,Vasl J,et al. Taxanes Inhibit Human TLR4 Signaling by Binding to MD-2[J]. FEBS Lett,2008,582(28):3929-3934.
42. [42]
  [42] Hutchinson M R,Zhang Y N,Shridhar M,et al. Evidence that Opioids may have Toll-Like Receptor 4 and MD-2 Effects[J]. Brain Behav Immun,2010,24(1):83-95.
43. [43]
  [43] Wang X H,Loram L C,Ramos K,et al. Morphine Activates Neuroinflammation in a Manner Parallel to Endotoxin[J]. PNAS,2012,109(16):6325-6330.
44. [44]
  [44] Lewis S S,Hutchinson M R,Rezvani N,et al. Evidence that Intrathecal Morphine-3-Glucuronide may Cause Pain Enhancement via Toll-Like Receptor 4/Md-2 and Interleukin-1 Beta[J]. Neuroscience,2010,165(2):569-583.
45. [45]
  [45] Loppnow H,Libby P,Freudenberg M,et al. Cytokine Induction by Lipopolysaccharide(LPS) Corresponds to Lethal Toxicity and is Inhibited by Nontoxic Rhodobacter Capsulatus LPS[J]. Infect Immun,1990,58(11):3743-3750.
46. [46]
  [46] Christ W J,Asano O,Robidoux A L,et al. E5531, a Pure Endotoxin Antagonist of High Potency[J]. Science,1995,268(5207):80-83.
47. [47]
  [47] Wasan K M,Strobel F W,Parrott S C,et al. Lipoprotein Distribution of a Novel Endotoxin Antagonist, E5531, in Plasma from Human Subjects with Various Lipid Levels[J]. Antimicrob Agents Chemother,1999,43(10):2562-2564.
48. [48]
  [48] Rossignol D P,Lynn M. Antagonism of in Vivo and ex Vivo Response to Endotoxin by E5564, a Synthetic Lipid A Analogue[J]. J Endotoxin Res,2002,8(6):483-488.
49. [49]
  [49] Mullarkey M,Rose J R,Bristol J,et al. Inhibition of Endotoxin Response by e5564, a Novel Toll-like Receptor 4-Directed Endotoxin Antagonist[J]. J Pharmacol Exp Ther,2003,304(3):1093-1102.
50. [50]
  [50] Lynn M,Rossignol D P,Wheeler J L,et al. Blocking of Responses to Endotoxin by E5564 in Healthy Volunteers with Experimental Endotoxemia[J]. J Infect Dis,2003,187(4):631-639.
51. [51]
  [51] Akashi S,Nagai Y,Ogata H,et al. Human MD-2 Confers on Mouse Toll-like Receptor 4 Species-Specific Lipopolysaccharide Recognition[J]. Int Immunol,2001,13(12):1595-1599.
52. [52]
  [52] Muroi M,Tanamoto K. Structural Regions of MD-2 That Determine the Agonist-Antagonist Activity of Lipid IVa[J]. J Biol Chem,2006,281(9):5484-5491.
53. [53]
  [53] Wang X,Cochran T A,Hutchinson M R,et al. Drug Addiction[M]. in Microglia in Health and Disease, Tremblay M-È and Sierra A, Editors. 2014,Springer New York:New York,NY. 299-317.
54. [54]
  [54] Selfridge B R,Wang X,Zhang Y,et al. Structure-Activity Relationships of (+)-Naltrexone-inspired Toll-like Receptor 4 (TLR4) Antagonists[J]. J Med Chem,2015,58(12):5038-5052.
55. [55]
  [55] Wang X,Zhang Y,Peng Y,et al. Pharmacological Characterization of the Opioid Inactive Isomers (+)-naltrexone and (+)-naloxone as Antagonists of Toll-like Receptor 4[J]. Br J Pharmacol,2016,173(5):856-869.
56. [56]
  [56] Yamada M,Ichikawa T,Ii M,et al. Discovery of Novel and Potent Small-Molecule Inhibitors of NO and Cytokine Production as Antisepsis Agents:Synthesis and Biological Activity of Alkyl 6-(N-substituted sulfamoyl)cyclohex-1-ene-1-carboxylate[J]. J Med Chem,2005,48(23):7457-7467.
57. [57]
  [57] Kawamoto T,Ii M,Kitazaki T,et al. TAK-242 Selectively Suppresses Toll-like Receptor 4-Signaling Mediated by the Intracellular Domain[J]. Eur J Pharmacol,2008,584(1):40-48.
58. [58]
  [58] Takashima K,Matsunaga N,Yoshimatsu M,et al. Analysis of Binding Site for the Novel Small-Molecule TLR4 Signal Transduction Inhibitor TAK-242 and Its Therapeutic Effect on Mouse Sepsis Model[J]. Br J Pharmacol,2009,157(7):1250-1262.
59. [59]
  [59] Mancek-Keber M,Jerala R. Structural Similarity Between the Hydrophobic Fluorescent Probe and Lipid A as a Ligand of MD-2[J]. FASEB J,2006,20(11):1836-1842.
60. [60]
  [60] Youn H S,Saitoh S I,Miyake K,et al. Inhibition of Homodimerization of Toll-like Receptor 4 by Curcumin[J]. Biochem Pharmacol,2006,72(1):62-69.
61. [61]
  [61] Gradisar H,Keber M M,Pristovsek P,et al. MD-2 as the Target of Curcumin in the Inhibition of Response to LPS[J]. J Leukocyte Biol,2007,82(4):968-974.
62. [62]
  [62] Park S H,Kyeong M S,Hwang Y,et al. Inhibition of LPS Binding to MD-2 co-Receptor for Suppressing TLR4-mediated Expression of Inflammatory Cytokine by 1-Dehydro-10-Gingerdione from Dietary Ginger[J]. Biochem Biophys Res Commun,2012,419(4):735-740.
63. [63]
  [63] Chu M,Ding R,Chu Z Y,et al. Role of Berberine in Anti-bacterial as a High-affinity LPS Antagonist Binding to TLR4/MD-2 Receptor[J]. BMC Complem Altern Med,2014,14(1):89-98.
64. [64]
  [64] Chen Y F,Shiau A L,Wang S H,et al. Zhankuic Acid A Isolated from Taiwanofungus Camphoratus is a Novel Selective TLR4/MD-2 Antagonist with Anti-inflammatory Properties[J]. J Immunol,2014,192(6):2778-2786.
1. [1]
  Xiaoxuan Yu , Wukun Liu . Practice of Ideological and Political Education in Medicinal Chemistry for Pharmacy Administration Major: A Case Study on the Discovery of Cisplatin’s Anticancer Function. University Chemistry, 2025, 40(4): 408-414. doi: 10.12461/PKU.DXHX202405200
2. [2]
  Jingzhao Cheng , Shiyu Gao , Bei Cheng , Kai Yang , Wang Wang , Shaowen Cao . 4-氨基-1H-咪唑-5-甲腈修饰供体-受体型氮化碳光催化剂的构建及其高效光催化产氢研究. Acta Physico-Chimica Sinica, 2024, 40(11): 2406026-. doi: 10.3866/PKU.WHXB202406026
3. [3]
  Yiming Liang , Ziyan Pan , Kin Shing Chan . One Drink, Two Tears in the Central Nervous System: The Perils of Disulfiram-Like Reactions. University Chemistry, 2025, 40(4): 322-325. doi: 10.12461/PKU.DXHX202406016
4. [4]
  Ziheng Zhuang , Xiao Xu , Kin Shing Chan . Superdrugs for Superbugs. University Chemistry, 2024, 39(9): 128-133. doi: 10.3866/PKU.DXHX202309040
5. [5]
  Bo YANG , Gongxuan LÜ , Jiantai MA . Corrosion inhibition of nickel-cobalt-phosphide in water by coating TiO₂ layer. Chinese Journal of Inorganic Chemistry, 2025, 41(2): 365-384. doi: 10.11862/CJIC.20240063
6. [6]
  Yan Xiao , Shuling Li , Yifan Li , Jianing Fan , Linlin Shi . Discovering the Beauty of Life: Adding Some “Ingredients” to Crystals. University Chemistry, 2024, 39(6): 366-372. doi: 10.3866/PKU.DXHX202312025
7. [7]
  Yi YANG , Shuang WANG , Wendan WANG , Limiao CHEN . Photocatalytic CO₂ reduction performance of Z-scheme Ag-Cu₂O/BiVO₄ photocatalyst. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 895-906. doi: 10.11862/CJIC.20230434
8. [8]
  Wei Zhong , Dan Zheng , Yuanxin Ou , Aiyun Meng , Yaorong Su . K原子掺杂高度面间结晶的g-C₃N₄光催化剂及其高效H₂O₂光合成. Acta Physico-Chimica Sinica, 2024, 40(11): 2406005-. doi: 10.3866/PKU.WHXB202406005
9. [9]
  Yi Yang , Xin Zhou , Miaoli Gu , Bei Cheng , Zhen Wu , Jianjun Zhang . S型ZnO/CdIn₂S₄光催化剂制备H₂O₂偶联苄胺氧化的超快电子转移飞秒吸收光谱研究. Acta Physico-Chimica Sinica, 2025, 41(6): 100064-. doi: 10.1016/j.actphy.2025.100064
10. [10]
  Zihan Lin , Wanzhen Lin , Fa-Jie Chen . Electrochemical Modifications of Native Peptides. University Chemistry, 2025, 40(3): 318-327. doi: 10.12461/PKU.DXHX202406089
11. [11]
  Zhao Lu , Hu Lv , Qinzhuang Liu , Zhongliao Wang . Modulating NH₂ Lewis Basicity in CTF-NH₂ through Donor-Acceptor Groups for Optimizing Photocatalytic Water Splitting. Acta Physico-Chimica Sinica, 2024, 40(12): 2405005-. doi: 10.3866/PKU.WHXB202405005
12. [12]
  Changsheng Lu . Discovering-and-Sharing Model: a Case of the Inorganic Chemistry Course in the Chemistry “101 Plan”. University Chemistry, 2024, 39(10): 78-83. doi: 10.12461/PKU.DXHX202408028
13. [13]
  Peng Zhan . Practice and Reflection in Training Medicinal Chemistry Graduate Students. University Chemistry, 2024, 39(6): 112-121. doi: 10.3866/PKU.DXHX202402022
14. [14]
  Zhibei Qu , Changxin Wang , Lei Li , Jiaze Li , Jun Zhang . Organoid-on-a-Chip for Drug Screening and the Inherent Biochemistry Principles. University Chemistry, 2024, 39(7): 278-286. doi: 10.3866/PKU.DXHX202311039
15. [15]
  Wenlong LI , Xinyu JIA , Jie LING , Mengdan MA , Anning ZHOU . Photothermal catalytic CO₂ hydrogenation over a Mg-doped In₂O_3-x catalyst. Chinese Journal of Inorganic Chemistry, 2024, 40(5): 919-929. doi: 10.11862/CJIC.20230421
16. [16]
  Zhilian Liu , Wengui Wang , Hongxiao Yang , Yu Cui , Shoufeng Wang . Ideological and Political Education Design for the Synthesis of Irinotecan Drug Intermediate 7-Ethyl Camptothecin. University Chemistry, 2024, 39(2): 89-93. doi: 10.3866/PKU.DXHX202306012
17. [17]
  Zheqi Wang , Yawen Lin , Shunliu Deng , Huijun Zhang , Jinmei Zhou . Antiviral Strategies: A Brief Review of the Development History of Small Molecule Antiviral Drugs. University Chemistry, 2024, 39(9): 85-93. doi: 10.12461/PKU.DXHX202403108
18. [18]
  Kun WANG , Wenrui LIU , Peng JIANG , Yuhang SONG , Lihua CHEN , Zhao DENG . Hierarchical hollow structured BiOBr-Pt catalysts for photocatalytic CO₂ reduction. Chinese Journal of Inorganic Chemistry, 2024, 40(7): 1270-1278. doi: 10.11862/CJIC.20240037
19. [19]
  Zeyu XU , Anlei DANG , Bihua DENG , Xiaoxin ZUO , Yu LU , Ping YANG , Wenzhu YIN . Evaluation of the efficacy of graphene oxide quantum dots as an ovalbumin delivery platform and adjuvant for immune enhancement. Chinese Journal of Inorganic Chemistry, 2024, 40(6): 1065-1078. doi: 10.11862/CJIC.20240099
20. [20]
  Hailang JIA , Hongcheng LI , Pengcheng JI , Yang TENG , Mingyun GUAN . Preparation and performance of N-doped carbon nanotubes composite Co₃O₄ as oxygen reduction reaction electrocatalysts. Chinese Journal of Inorganic Chemistry, 2024, 40(4): 693-700. doi: 10.11862/CJIC.20230402

Get Citation

PDF

XML

Metrics

PDF Downloads(0)
Abstract views(311)
HTML views(38)

通讯作者: 陈斌, bchen63@163.com

1.
沈阳化工大学材料科学与工程学院沈阳 110142