Improving the Adjuvanticity of Small Molecule Immune Potentiators Using Covalently Linked NF-κB Modulators.

Small molecule immune potentiators (SMIPs) such as imidazoquinolinone derivatives that activate Toll-like receptor (TLR) 7/8 have immense potential as vaccine adjuvants and as antitumor agents. However, these molecules have high bioavailability that results in unacceptable levels of systemic inflammation due to adjuvant toxicity, thereby greatly limiting their use. To address this challenge, here we report the design and synthesis of novel imidazoquinolinone-NF-κB immunomodulator dimers.

A synthetic pathogen mimetic molecule induces a highly amplified synergistic immune response activation of multiple signaling pathways.

The current understanding of how the immune system processes complex information during natural infections is yet to be exploited for the molecular design of potent immune activators. Here, we address this challenge by design of a pathogen-mimetic molecule that simultaneously co-activates cell-surface active, endosomal and cytosolic immune receptors.

Small Molecule NF-κB Inhibitors as Immune Potentiators for Enhancement of Vaccine Adjuvants.

Adjuvants are added to vaccines to enhance the immune response and provide increased protection against disease. In the last decade, hundreds of synthetic immune adjuvants have been created, but many induce undesirable levels of proinflammatory cytokines including TNF-α and IL-6. Here we present small molecule NF-κB inhibitors that can be used in combination with an immune adjuvant to both decrease markers associated with poor tolerability and improve the protective response of vaccination.