Structure-Activity Relationships Toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist

Toll-like receptor (TLR)-7 agonists are immunostimulatory vaccine adjuvants. A systematic structure-activity relationship (SAR) study of TLR7-active 1-benzyl-2-butyl-1-imidazo[4,5-]quinolin-4-amine led to the identification of a potent hTLR7-specific -hydroxymethyl IMDQ with an EC value of 0.22 μM. The SAR investigation also resulted in the identification of TLR7 selective carboxamide with EC values of 0.32 μM for hTLR7 and 18.25 μM for hTLR8. In the vaccination study, TLR7-specific compound 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 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.