Enantioselective Effect of Chiral Small Molecules in SARS‐CoV‐2 Vaccine‐Induced Immune Response

• Published in: Angewandte Chemie Vol. 135; no. 28
• Main Authors: Zhou, Zhengmiao, Zhang, Yufang, Ji, Honghan, Jin, Yu, Chen, Sisi, Duan, Pengfei, Liu, Ye
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 10.07.2023
• Subjects: Adjuvant; Adjuvants; Antigens; Chemical synthesis; Chemistry; Chirality; Dendritic cells; Enantiomers; Immune response; Immune system; Immunology; Internalization; Macrophages; Neutralization; SARS-CoV-2 Vaccine; Severe acute respiratory syndrome; Severe acute respiratory syndrome coronavirus 2; Small Molecule; TLR7 protein; Toll-like receptors; Vaccines
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202301085

Although numerous chiral small molecules have been discovered and synthesized, the investigation on their enantioselective immunological effects remains limited. In this study, we designed and synthesized a pair of small molecule enantiomers (R/S‐ResP) by covalently bonding two immunostimulators (resiquimod/Res) onto a planar chiral framework (paracyclophane/P). Notably, we found that S‐ResP exhibits a 4.05‐fold higher affinity for toll‐like receptor 7 (TLR7) than R‐ResP, thereby more effectively enhancing the functions of dendritic cells and macrophages in cytokine secretion and antigen internalization. Furthermore, we observed that S‐ResP significantly enhances RBD antigen‐induced cross‐neutralization against various SARS‐CoV‐2 strains compared to R‐ResP. These findings demonstrate the enantioselective effects of small molecules on regulating vaccine‐induced immune responses and emphasize the significance of chirality in designing small molecular adjuvants. Via decorating immunostimulatory small‐molecule resiquimod (R848) on the chiral framework R/S‐paracyclophane, we synthesized planar‐chiral enantiomers R/S‐ResP. For SARS‐CoV‐2 vaccine, in comparison to R‐ResP, S‐ResP exhibited a significant enhancement for vaccine‐induced cross‐neutralization against various viral strains. This study revealed the importance of enantioselective effect in the design and construction of chiral small molecule adjuvants.