Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure–activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine led to the identification of a potent hTLR7-specific p-hydroxymethyl IMDQ 23 with an EC₅₀ value of 0.22 μM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide 12 with EC₅₀ values of 0.32 μM for hTLR7 and 18.25 μM for hTLR8. In the vaccination study, TLR7-specific compound 23 alone or combined with alum (aluminum hydroxide wet gel) showed adjuvant activity for a spike protein immunogen in mice, with enhanced anti-spike antibody production. Interestingly, the adjuvant system comprising carboxamide 12 and alum showed prominent adjuvant activity with high levels of IgG1, IgG2b, and IgG2c in immunized mice, confirming a balanced Th1/Th2 response. In the absence of any apparent toxicity, the TLR7 selective agonists in combination with alum may make a suitable vaccine adjuvant.

中文翻译：

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高效选择性人类 Toll 样受体 7 激动剂的结构-活性关系的鉴定


Toll 样受体 (TLR)-7 激动剂是免疫刺激疫苗佐剂。对 TLR7 活性 1-benzyl-2-丁基-1H-imidazo[4,5-c]quinolin-4-amine 的系统结构-活性关系 (SAR) 研究导致鉴定出有效的 hTLR7 特异性 p-羟甲基IMDQ 23，EC ₅₀ 值为 0.22 μM。 SAR 研究还鉴定出 TLR7 选择性甲酰胺 12，hTLR7 的 EC ₅₀ 值为 0.32 μM，hTLR8 的 EC ₅₀ 值为 18.25 μM。在疫苗接种研究中，单独的 TLR7 特异性化合物 23 或与明矾（氢氧化铝湿凝胶）组合对小鼠中的刺突蛋白免疫原显示出佐剂活性，并增强抗刺突抗体的产生。有趣的是，包含羧酰胺 12 和明矾的佐剂系统在免疫小鼠中表现出显着的佐剂活性，具有高水平的 IgG1、IgG2b 和 IgG2c，证实了平衡的 Th1/Th2 反应。在没有任何明显毒性的情况下，TLR7选择性激动剂与明矾组合可以制成合适的疫苗佐剂。