Hussein Waleed M, Liu Tzu-Yu, Skwarczynski Mariusz, Toth Istvan
The University of Queensland, School of Chemistry and Molecular Biosciences , St. Lucia, Brisbane, Qld 4072 , Australia.
Expert Opin Ther Pat. 2014 Apr;24(4):453-70. doi: 10.1517/13543776.2014.880691. Epub 2014 Jan 24.
Toll-like receptors (TLRs) are a crucial part of the innate immunity and present the first line of defense against pathogens. In humans, there are ten TLRs, with TLR3, 7, 8 and 9 located in intracellular vesicles and the remaining expressed on the cell surface. These transmembrane protein receptors recognize a wide range of pathogen components. A large number of TLR agonists, either derived from pathogen components or modified synthetic molecules, were developed and investigated for their ability to stimulate an immune response.
This review includes an updated summary (2011 - 2013) of TLR agonists that have been published in patent applications and/or progressed to clinical studies, with an emphasis on their chemical structure, immune response, prophylactic and therapeutic outcomes.
A number of factors have contributed to the design and development of TLR agonists such as solving the crystal structures of TLR bound to their ligands, improvements in our understanding of the signaling pathway activated after TLR stimulation and the identification of the native ligands of all human TLRs. Some of the TLR agonists have been approved for human use by the FDA while others have reached clinical studies in Phases I, II and III. Generally, immunotherapy based on TLR agonists is very promising for the prevention and/or treatment of several disorders including cancer, allergy and microbial infections. However, many TLR agonists were withdrawn from further studies as they either lacked efficacy or caused serious side effects.
Toll样受体（TLRs）是固有免疫的关键组成部分，是抵御病原体的第一道防线。在人类中，有十种TLR，其中TLR3、7、8和9位于细胞内囊泡中，其余的在细胞表面表达。这些跨膜蛋白受体可识别多种病原体成分。人们开发并研究了大量源自病原体成分或经过修饰的合成分子的TLR激动剂，以评估它们刺激免疫反应的能力。
本综述包括已在专利申请中公布和/或已进入临床研究阶段的TLR激动剂的最新总结（2011 - 2013年），重点介绍其化学结构、免疫反应、预防和治疗效果。
多种因素推动了TLR激动剂的设计和开发，如解析TLR与其配体结合的晶体结构、增进对TLR刺激后激活的信号通路的理解以及鉴定所有人类TLR的天然配体。一些TLR激动剂已获美国食品药品监督管理局（FDA）批准用于人类，其他一些则已进入I期、II期和III期临床研究。总体而言，基于TLR激动剂的免疫疗法在预防和/或治疗包括癌症、过敏和微生物感染在内的多种疾病方面前景广阔。然而，许多TLR激动剂因缺乏疗效或导致严重副作用而停止进一步研究。
