Adjuvants are essential components of subunit vaccines capable of promoting potent and persistent immune responses when combined with antigen or epitope vaccines. However, only a few vaccine adjuvants have been approved by the FDA for human use so far. Therefore, there is still an urgent need to develop novel adjuvants for potential applications in clinical trials. Among the increasing number of studies on innate immunity including pattern recognition receptors, stimulator of interferon genes (STING) agonists have found favor in cancer indications and as vaccine adjuvants inducing type I interferon (IFN-I) response and proinflammatory cytokine production. Cyclic dinucleotide (CDN) cyclic GMP-AMP (cGAMP) is the most potent natural agonist of STING. Given the breadth of STINGs immune functions, several STING agonists, such as endogenous ligands have been used in diverse clinical research for immunogenic tumor clearance, antiviral treatments, and vaccine adjuvants. However, there is a continued need to develop novel adjuvants to improve subunit vaccine efficacy and safely potentiate immune responses. Herein, we describe the structure-activity relationship study and synthesis of a series of novel non-CDN small-molecule STING agonists 1 including 1d as a highly potent human STING agonist with an EC50 value of 1.2-1.8 µM. These novel agonists are more potent or retain equivalent Sting activity to the corresponding known synthetic Sting agonist diABZI. We also confirmed STING specificity of these novel agonists by abolishing STING signaling pathways in the STING knockout cells.

Development of novel STING pathway agonists as vaccine adjuvants

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