Fernández-Tejada Alberto, Chea Eric K, George Constantine, Pillarsetty NagaVaraKishore, Gardner Jeffrey R, Livingston Philip O, Ragupathi Govind, Lewis Jason S, Tan Derek S, Gin David Y
Molecular Pharmacology & Chemistry Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York 10065, USA.
Nat Chem. 2014 Jul;6(7):635-43. doi: 10.1038/nchem.1963. Epub 2014 Jun 1.
Adjuvants are materials added to vaccines to enhance the immunological response to an antigen. QS-21 is a natural product adjuvant under investigation in numerous vaccine clinical trials, but its use is constrained by scarcity, toxicity, instability and an enigmatic molecular mechanism of action. Herein we describe the development of a minimal QS-21 analogue that decouples adjuvant activity from toxicity and provides a powerful platform for mechanistic investigations. We found that the entire branched trisaccharide domain of QS-21 is dispensable for adjuvant activity and that the C4-aldehyde substituent, previously proposed to bind covalently to an unknown cellular target, is also not required. Biodistribution studies revealed that active adjuvants were retained preferentially at the injection site and the nearest draining lymph nodes compared with the attenuated variants. Overall, these studies have yielded critical insights into saponin structure-function relationships, provided practical synthetic access to non-toxic adjuvants, and established a platform for detailed mechanistic studies.
佐剂是添加到疫苗中以增强对抗原免疫反应的物质。QS-21是一种正在众多疫苗临床试验中研究的天然产物佐剂，但其使用受到稀缺性、毒性、不稳定性以及神秘的分子作用机制的限制。在此，我们描述了一种最小化QS-21类似物的开发，该类似物将佐剂活性与毒性分离，并为机制研究提供了一个强大的平台。我们发现QS-21的整个分支三糖结构域对于佐剂活性是可有可无的，并且先前提出的与未知细胞靶点共价结合的C4-醛取代基也是不需要的。生物分布研究表明，与减毒变体相比，活性佐剂优先保留在注射部位和最近的引流淋巴结中。总体而言，这些研究对皂苷结构-功能关系产生了关键见解，为无毒佐剂提供了实际的合成途径，并建立了一个用于详细机制研究的平台。
