title: Therapeutic Developments Targeting Toll-like Receptor-4-Mediated Neuroinflammation.
abstract: Toll-like receptors (TLRs) have been shown to play an important role in the immune system, which warrants study of their remarkable potential as pharmacological targets. Activation of TLRs requires participation from specific pathogen-associated molecular patterns (PAMPs) and accessory proteins such as myeloid differentiation protein 2 (MD2), lipopolysaccharide binding protein (LBP), and cluster differentiation antigen 14 (CD14). Assembly of the TLR4-MD2-LPS complex is essential in TLR4 activation. Recent studies have revealed that TLR4 activation is a significant trigger of signal transmission pathways in the nervous system, which could result in chronic pain as well as opioid tolerance and dependence. Researchers of the molecular structure of TLRs and their accessory proteins have opened a door to syntheses of TLRs agonists and antagonists, such as eritoran. Small-molecule modulators of TLR4, such as MD2-I and tricyclic antidepressants, offer more promising prospects than peptides, given their convenience in oral administration and lower cost. Herein we mainly discuss the mechanisms and clinical prospects of TLR4 agonists and antagonists.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100032, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, 80309-0596, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Csakai
authors.affiliation: Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China.|Physikalisch-Astronomische Fakultät, Abbe School of Photonics, Jena, 07743, Germany.
authors.forename: Jialin
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Key Laboratory of Rheumatology and Clinical Immunology, Ministry of Education, Beijing, 100032, China. zhangfccra@aliyun.com.
authors.forename: Fengchun
authors.initials: F
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry and BioFrontiers Institute, University of Colorado, Boulder, CO, 80309-0596, USA. hubert.yin@colorado.edu.|Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing, 100082, China. hubert.yin@colorado.edu.
authors.forename: Hang
authors.initials: H
authors.lastname: Yin
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D054852:Small Molecule Libraries; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4
keywords: accessory proteins; analgesia; drug discovery; inflammation; neuropathic pain; toll-like receptors