Rational design of small molecules as vaccine adjuvants
Rational design of small molecules as vaccine adjuvants
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DOI：
10.1126/scitranslmed.3009980
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发表时间：
2014-11-19
影响因子：
17.1
通讯作者：
Valiante, Nicholas M.
中科院分区：
文献类型：
--
作者：
Wu, Tom Y. -H.;Singh, Manmohan;Valiante, Nicholas M.
佐剂主要通过激活先天免疫和促进炎症来提高疫苗效力。限制这种炎症的副作用是人类疫苗佐剂使用的主要障碍。由于对佐剂机制的了解不足以及历史上佐剂发现和开发的经验性质，佐剂安全性一直难以提高。我们描述了合理优化以 Toll 样受体 7 作为佐剂的小分子免疫增强剂 (SMIP) 的新原理，预计其治疗指数会增加。与传统药物不同，基于 SMIP 的佐剂需要具有有限的生物利用度并保持局部性以获得最佳疗效。这些特征还会导致时间和空间上受限的炎症，从而减少副作用。通过药物和制剂化学以及广泛的免疫药理学，我们表明，基于 SMIP 的佐剂在几乎没有或没有全身暴露、局部先天免疫激活和体内停留时间短的情况下，可以增加体内效力。这项工作提供了一种系统且可推广的方法来设计用作疫苗佐剂的小分子。
Adjuvants increase vaccine potency largely by activating innate immunity and promoting inflammation. Limiting the side effects of this inflammation is a major hurdle for adjuvant use in vaccines for humans. It has been difficult to improve on adjuvant safety because of a poor understanding of adjuvant mechanism and the empirical nature of adjuvant discovery and development historically. We describe new principles for the rational optimization of small-molecule immune potentiators (SMIPs) targeting Toll-like receptor 7 as adjuvants with a predicted increase in their therapeutic indices. Unlike traditional drugs, SMIP-based adjuvants need to have limited bioavailability and remain localized for optimal efficacy. These features also lead to temporally and spatially restricted inflammation that should decrease side effects. Through medicinal and formulation chemistry and extensive immunopharmacology, we show that in vivo potency can be increased with little to no systemic exposure, localized innate immune activation and short in vivo residence times of SMIP-based adjuvants. This work provides a systematic and generalizable approach to engineering small molecules for use as vaccine adjuvants.