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Aryl Trehalose Derivatives as Vaccine Adjuvants for Mycobacterium tuberculosis.
Journal of Medicinal Chemistry ( IF 7.3 ) Pub Date : 2019-12-20 , DOI: 10.1021/acs.jmedchem.9b01598
Kendal T. Ryter , George Ettenger , Omer K. Rasheed , Cassandra Buhl , Robert Child , Shannon M. Miller , David Holley , Alyson J. Smith , Jay T. Evans

Mycobacterium tuberculosis (Mtb) continues to be a major health threat worldwide, and the development of Mtb vaccines could play a pivotal role in the prevention and control of this devastating epidemic. Th17-mediated immunity has been implicated in disease protection correlates of immune protection against Mtb. Currently, there are no approved adjuvants capable of driving a Th17 response in a vaccine setting. Recent clinical trial results using trehalose dibehenate have demonstrated a formulation-dependant proof of concept adjuvant system CAF01 capable of inducing long-lived protection. We have discovered a new class of Th17-inducing vaccine adjuvants based on the natural product Brartemicin. We synthesized and evaluated the capacity of a library of aryl trehalose derivatives to drive immunostimulatory reresponses and evaluated the structure-activity relationships in terms of the ability to engage the Mincle receptor and induce production of innate cytokines from human and murine cells. We elaborated on the structure-activity relationship of the new scaffold and demonstrated the ability of the lead entity to induce a pro-Th17 cytokine profile from primary human peripheral blood mononuclear cells and demonstrated efficacy in generating antibodies in combination with tuberculosis antigen M72 in a mouse model.

中文翻译:

芳基海藻糖衍生物作为结核分枝杆菌的疫苗佐剂。

结核分枝杆菌(Mtb)仍然是世界范围内的主要健康威胁,Mtb疫苗的开发可能在预防和控制这一毁灭性流行中起关键作用。Th17介导的免疫反应与针对Mtb的免疫保护的疾病保护相关。目前,尚无批准的佐剂能够在疫苗中引发Th17应答。使用海藻糖二山hen酸酯的最新临床试验结果表明,该配方佐剂体系CAF01具有配方依赖性,可诱导长期保护。我们已经发现了一种基于天然产物布拉替米星的新型Th17诱导疫苗佐剂。我们合成并评估了芳基海藻糖衍生物库驱动免疫刺激反应的能力,并根据与Mincle受体结合并诱导人和鼠细胞产生先天细胞因子的能力,评估了结构-活性关系。我们详细阐述了新支架的构效关系,并证明了先导实体从原代人外周血单核细胞诱导前Th17细胞因子谱的能力,并证明了在小鼠中与结核抗原M72结合产生抗体的功效模型。
更新日期:2019-12-20
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