Schematic and characterization of tri-agonist compound, Indole_Lox_CpG. (a) Chemical structure of covalently conjugated tri-agonist compound (Indole_Lox_CpG) (left). Diagram illustrating how each TLR agonist (pyrimido-indole, loxoribine, or CpG-ODN) and the corresponding combinations (Indole_Lox, Lox_CpG, or Indole_CpG) contributed to innate immune activation (right). (b) Confirmation of synthesized Indole_Lox_CpG via MALDI-TOF. (c) Analysis of Indole_Lox_CpG via gel electrophoresis: CpG-ODN1826 reference (lane 1) and Indole_Lox_CpG reaction mixture (lane 2). Tri-agonist was extracted from the gel and isolated as purified Indole_Lox_CpG.
Some vaccines, like the flu shot, contain a dead or weakened version of the disease-causing pathogen. Other vaccines, like those for hepatitis b and meningitis, contain just a protein, or other molecule (an “antigen”) unique to the microbe. When there is a whole pathogen, the innate immune system is strongly activated, which includes alerting cellular watchmen called the toll-like receptors (TLRs). Antigen-based vaccines do not cause as strong a response, but they produce fewer side effects. Thus, an adjuvant is usually added to antigen-based vaccines to boost their effectiveness. A common adjuvant is a TLR agonist, or activator. In nature, multiple TLR activators work together to effectively direct the immune system. Aaron Esser-Kahn and colleagues investigated whether they could probe this biological machinery and improve the efficacy of antigen-based vaccines.
The researchers suspected that how the TLR agonists were arranged in space could affect their activity. So, they synthesized probes that displayed 3 different TLR agonists with a defined spatial orientation ie they covalently conjugated 3 TLR agonists (TLR4, 7, and 9) to a small molecule core to probe the spatial arrangement of the agonists. Treating immune cells with the linked agonists increased activation of the transcription factor NFκB and enhanced and directed immune related cytokine production and gene expression beyond cells treated with an unconjugated mixture of the same 3 agonists. The use of TLR signaling inhibitors and knockout studies confirmed that the tri-agonist molecule activated multiple signaling pathways leading to the observed higher activity
In addition, by deconstructing the three-way activator into their 2 component parts, the team studied which components are most important and which arms of the immune response they activate. Esser-Kahn notes that this information will help researchers design better vaccines. http://www.eurekalert.org/pub_releases/2015-10/acs-ati102315.php
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