Directing the Immune System with Chemical Compounds

Abstract

Agonists of immune cell receptors direct innate and adaptive immunity. These agonists range in size and complexity from small molecules to large macromolecules. Here, agonists of a class of immune cell receptors known as the Toll-Like Receptors (TLRs) are highlighted focusing on the distinctive molecular moieties that pertain to receptor binding and activation. How the structure and combined chemical signals translate into a variety of immune responses remain major questions in the field. In this structure-focused review, we outline potential areas where the tools of chemical biology could help decipher the emerging molecular codes that direct immune stimulation.

pH-degradable imidazoquinoline-ligated nanogels for lymph node-focused immune activation

“…Especially promising in this context are agonists of the endosomal TLR7 and TLR8, which typically recognize singlestranded RNAs generated during viral infection (4) but can also be activated by synthetic small-molecule agonists (5). Molecular adjuvants (6, 7) that are agonists of TLR7/8 indeed activate a broad spectrum of antigen-presenting cells, both in mice (only TLR7) and humans, and typically induce high levels of type I IFN and IL-12, the most vital cytokines to drive the Th1 and cytotoxic T-cell responses required to combat intracellular infections and cancer (7,8).Due to their pharmacokinetic profile, most molecular adjuvants rapidly diffuse after administration and evoke systemic inflammatory responses that cause dose-limiting toxicity (9, 10). In the context of intratumoral administration, these dose-limiting toxicities prevent these compounds from reaching the necessary intratumoral concentration to yield real therapeutic benefit.…”

“…Especially promising in this context are agonists of the endosomal TLR7 and TLR8, which typically recognize singlestranded RNAs generated during viral infection (4) but can also be activated by synthetic small-molecule agonists (5). Molecular adjuvants (6,7) that are agonists of TLR7/8 indeed activate a broad spectrum of antigen-presenting cells, both in mice (only TLR7) and humans, and typically induce high levels of type I IFN and IL-12, the most vital cytokines to drive the Th1 and cytotoxic T-cell responses required to combat intracellular infections and cancer (7,8).…”

Immune Response Modulation of Conjugated Agonists with Changing Linker Length

“…2 Thereafter, the receptors induce a signaling cascade initiating the production of cytokines and costimulatory molecules in innate immune cells, ultimately activating the adaptive immune system. 3 Activating multiple TLRs on innate immune cells can lead to synergies that direct the adaptive immune response. 4 Controlling these synergies to enhance and direct immune signals is an ongoing challenge.…”

Big opportunities for small molecules in immuno-oncology

“…The majority of trials have examined agonists of endosomal TLRs (TLR3, TLR7, TLR8 and TLR9). Small-molecule heterocyclics, such as the imidazoquinolines, are recognized as nucleoside agonists by TLR7 and TLR8, which distinguishes these from TLR3 and TLR9 for which only oligonucleotide agonists have been discovered 131 . The antitumour effects of TLR7 and TLR8 agonists are primarily mediated by the activation of dendritic cells and natural killer cells to directly kill tumour cells, and by the suppression of T Reg cells 132 .…”