Synthetic agonists of Toll-like receptors 7, 8 and 9
Synthetic agonists of Toll-like receptors 7, 8 and 9
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DOI：
10.1042/bst0351461
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发表时间：
2007-12-01
影响因子：
3.9
通讯作者：
Kandimalla, E. R.
中科院分区：
文献类型：
--
作者：
Agrawal, S.;Kandimalla, E. R.
TLR（Toll样受体）是诱导针对感染的保护性免疫应答的先天性免疫受体家族。含有未甲基化的III基序的单链病毒RNA和细菌DNA分别是TLR 7和TLR 8和9的配体。我们已经进行了广泛的DNA和RNA为基础的化合物的结构-活性关系的研究，以阐明这些TLR介导的免疫反应的核苷酸基序和结构的影响。这些研究使我们设计了新的基于DNA和RNA的化合物，它们分别作为TLR 9和TLR 7和8的有效激动剂。这些新的合成激动剂产生不同的免疫反应谱，这取决于它们的结构和核苷酸基序。用这些新的基于DNA和RNA的激动剂以期望的方式调节TLR介导的免疫应答的能力可以允许单独或与其他治疗剂组合靶向广泛的疾病，包括癌症、哮喘、过敏和感染，以及它们作为疫苗佐剂的用途。IMO-2055是我们的第一个主要候选药物，是一种TLR 9激动剂，目前正在肿瘤患者中进行临床评估。第二个候选物，IMO-2125，也是一种TLR 9激动剂，已被证明在非人灵长类动物中诱导高水平和持续水平的IFN（干扰素），并正在HepC感染的人类受试者中进行评估。
TLRs (Toll-like receptors) are a family of innate immune receptors that induce protective immune responses against infections. Single-stranded viral RNA and bacterial DNA containing unmethylated Ill motifs are the ligands for TLR7 and TLR8 and 9 respectively. We have carried out extensive structure-activity relationship studies of DNA- and RNA-based compounds to elucidate the impact of nucleotide motifs and structures on these TLR-mediated immune responses. These studies have led us to design novel DNA- and RNA-based compounds, which act as potent agonists of TLR9 and TLR7 and 8 respectively. These novel synthetic agonists produce different immune response profiles depending on the structures and nucleotide motifs present in them. The ability to modulate TLR-mediated immune responses with these novel DNA- and RNA-based agonists in a desired fashion may allow targeting a broad range of diseases, including cancers, asthma, allergies and infections, alone or in combination with other therapeutic agents, and their use as adjuvants with vaccines. IMO-2055, our first lead candidate, is a TLR9 agonist that is currently in clinical evaluation in oncology patients. A second candidate, IMO-2125, is also a TLR9 agonist that has been shown to induce high and sustained levels of IFN (interferon) in non-human primates and is being evaluated in HepC-infected human subjects.