Discovery of Self‐Assembling Small Molecules as Vaccine Adjuvants

Abstract

Immune potentiators, termed adjuvants, trigger early innate immune responses to ensure the generation of robust and long‐lasting adaptive immune responses of vaccines. Presented here is a 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 nanoassembly potently elicits innate immune responses in macrophages and dendritic cells. Functional and mechanistic analyses indicate that the virus‐like assembly enters the 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 pave the way for a new approach to discovering and designing self‐assembling small‐molecule adjuvants against pathogens, including emerging viruses.

Materials engineering strategies for cancer vaccine adjuvant development

“…Notably, the small molecule of cholicamide is distinct from nucleoside deoxycholate derivatives such as imidazoquinolines, but the cholicamide assemblies can bind to the RNA-binding pocket of TLR7. 91 In a subsequent study, the researchers investigated the application of self-assembled cholicamide as an antigen carrier. They found that the assemblies of antigen-cholicamide conjugates with cholicamide could induce high levels of MHC II presentation of antigen peptides and cytokine release.…”

Matthew effect: General design strategy of ultra‐fluorogenic nanoprobes with amplified dark–bright states in aggregates

“…In this regard, we consider aggregation, a spontaneous phenomenon of hydrophobic molecules in aqueous systems, will be an effective solution to increase tetrazine-chromophore proximity and interactions, enhancing tetrazine quenching effects. [23,53] However, most conventional planar fluorophores suffer from aggregation-caused quenching (ACQ) effect, [54][55][56] which diminishes post-click turn-on emission in aggregates, making it difficult to apply this aggregation strategy for fluorogenic probe designs. Therefore, we focused on aggregation-induced emission luminogens (AIEgens), a series of dyes that exhibit weak emission in dilute solutions but significantly enhanced emission in the aggregate state, to achieve this strategy.…”

Development of synthetic, self-adjuvanting, and self-assembling anticancer vaccines based on a minimal saponin adjuvant and the tumor-associated MUC1 antigen

“…mass spectrometry, liquid chromatography, nuclear magnetic resonance), while drastically minimizing batch-to-batch variations. Leveraging on synthetic building blocks and orthogonal ligation chemistries, unimolecular multicomponent anticancer vaccines can benet from efficient "plug-and-play" design approaches that facilitate in vivo evaluation of various B-cell antigens, 29,30 T-cell epitopes, [31][32][33] adjuvants, [34][35][36] linkers/ spacers, 37,38 and scaffolds. 39,40 Over the last few years, growing attention has been paid to the role of vaccine adjuvants, not only as enhancers but also as "directors" of the immune response.…”