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Discovery of Self-Assembling Small Molecules as Vaccine Adjuvants

Immune potentiators, termed adjuvant, trigger early innate immune responses to ensure the generation of robust and long-lasting adaptive immune responses of vaccines. Here we present study that takes advantage of a self-assembling small molecule library for the development of a novel vaccine adjuvant. Cell-based screening of the library and subsequent structural optimization led to the discovery of a simple, chemically tractable deoxycholate derivative (molecule 6 , also named cholicamide) whose well-defined nano-assembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus-like assembly is engulfed inside cells and stimulates the innate immune response through toll-like receptor 7 (TLR7), an endosomal TLR that detects single-stranded viral RNA. As an influenza vaccine adjuvant in mice, molecule 6 was as potent as Alum, a clinically used adjuvant. The studies described here paves the way for a new approach to discovering and designing self-assembling small-molecule adjuvants against pathogens, including emerging viruses.

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