Heine Holger, Zamyatina Alla
Research Group Innate Immunity, Research Center Borstel-Leibniz Lung Center, Airway Research Center North (ARCN), German Center for Lung Research (DZL), Parkallee 22, 23845 Borstel, Germany.
Department of Chemistry, University of Natural Resources and Life Sciences, Muthgasse 18, 1190 Vienna, Austria.
Pharmaceuticals (Basel). 2022 Dec 23;16(1):23. doi: 10.3390/ph16010023.
The Toll-like receptor 4 (TLR4) signaling pathway plays a central role in the prompt defense against infectious challenge and provides immediate response to Gram-negative bacterial infection. The TLR4/MD-2 complex can sense and respond to various pathogen-associated molecular patterns (PAMPs) with bacterial lipopolysaccharide (LPS) being the most potent and the most frequently occurring activator of the TLR4-mediated inflammation. TLR4 is believed to be both a friend and foe since improperly regulated TLR4 signaling can result in the overactivation of immune responses leading to sepsis, acute lung injury, or pathologic chronic inflammation involved in cancer and autoimmune disease. TLR4 is also considered a legitimate target for vaccine adjuvant development since its activation can boost the adaptive immune responses. The dual action of the TLR4 complex justifies the efforts in the development of both TLR4 antagonists as antisepsis drug candidates or remedies for chronic inflammatory diseases and TLR4 agonists as vaccine adjuvants or immunotherapeutics. In this review, we provide a brief overview of the biochemical evidences for possible pharmacologic applications of TLR4 ligands as therapeutics and report our systematic studies on the design, synthesis, and immunobiological evaluation of carbohydrate-based TLR4 antagonists with nanomolar affinity for MD-2 as well as disaccharide-based TLR4 agonists with picomolar affinity for the TLR4/MD-2 complex.
Toll样受体4（TLR4）信号通路在针对感染性挑战的快速防御中起核心作用，并能对革兰氏阴性菌感染做出即时反应。TLR4/MD-2复合物可感知并响应各种病原体相关分子模式（PAMP），其中细菌脂多糖（LPS）是TLR4介导的炎症最有效且最常见的激活剂。TLR4被认为既是“朋友”也是“敌人”，因为TLR4信号通路调节不当会导致免疫反应过度激活，进而引发败血症、急性肺损伤，或导致涉及癌症和自身免疫性疾病的病理性慢性炎症。TLR4也被视为疫苗佐剂开发的合理靶点，因为其激活可增强适应性免疫反应。TLR4复合物的双重作用证明了开发TLR4拮抗剂作为抗败血症药物候选物或慢性炎症疾病治疗药物，以及开发TLR4激动剂作为疫苗佐剂或免疫治疗药物的努力是合理的。在本综述中，我们简要概述了TLR4配体作为治疗药物可能的药理学应用的生化证据，并报告了我们对基于碳水化合物的对MD-2具有纳摩尔亲和力的TLR4拮抗剂以及对TLR4/MD-2复合物具有皮摩尔亲和力的基于二糖的TLR4激动剂的设计、合成和免疫生物学评价的系统研究。
