Discovery of Self‐Assembling Small Molecules as Vaccine Adjuvants

• Published in: Angewandte Chemie International Edition 2021-01, Vol.60 (2), p.961-969
• Main Authors: Jin, Shuyu, Vu, Hue Thi, Hioki, Kou, Noda, Naotaka, Yoshida, Hiroki, Shimane, Toru, Ishizuka, Shigenari, Takashima, Ippei, Mizuhata, Yoshiyuki, Beverly Pe, Kathleen, Ogawa, Tetsuya, Nishimura, Naoya, Packwood, Daniel, Tokitoh, Norihiro, Kurata, Hiroki, Yamasaki, Sho, Ishii, Ken J., Uesugi, Motonari
• Format: Article
• Language: English
• Subjects: Adaptive immunity; Adjuvants; Adjuvants, Immunologic - chemistry; Amides - chemistry; Amides - immunology; Amides - pharmacology; Animals; Antibodies, Viral - blood; Antibodies, Viral - immunology; Assembling; chemical biology; Dendritic cells; Dendritic Cells - cytology; Dendritic Cells - immunology; Dendritic Cells - metabolism; Deoxycholic Acid - chemistry; Drug Evaluation, Preclinical; Fluorescent Dyes - chemistry; Immune response; Immune system; Immunity, Innate; Immunoglobulin G - blood; Influenza; Influenza Vaccines - chemistry; Influenza Vaccines - immunology; Innate immunity; Interleukin-6 - metabolism; Libraries; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; nanostructures; Nanostructures - chemistry; Optimization; Proteins; RAW 264.7 Cells; Ribonucleic acid; RNA; self-assembly; Structure-Activity Relationship; TLR7 protein; Toll-Like Receptor 7 - metabolism; Toll-like receptors; Vaccines; viruses
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202011604

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. Vaccine adjuvants are required for the generation of robust and long‐lasting immune responses of antigen vaccines. Screening of a newly constructed chemical library of self‐assembling molecules led to the rapid discovery of cholicamide (6), as a potent vaccine adjuvant. Just like viruses, the nanoassembly of cholicamide enters the cells and is recognized by an endosomal Toll‐like receptor to elicit potent innate immune responses.