Structural Evolution and Translational Potential for Agonists and Antagonists of Endosomal Toll-like Receptors

Abstract

Toll-like receptors (TLRs) are members of a large family of evolutionarily conserved pattern recognition receptors (PRRs), which serve as key components of the innate immune system by playing a pivotal role in sensing "nonself" ligands. Endosomal TLRs (TLR3, TLR7, TLR8, and TLR9) can recognize pathogen-derived nucleic acid and initiate an innate immune response because they react against both self-and non-self-origin nucleic acid molecules. Accordingly, both receptor agonists and antagonists are potentially useful in disparate clinical contexts and thus are globally sought after. Recent research has revealed that agonists and antagonists share an overlapping binding region. This Perspective highlights rational medicinal chemistry approaches to elucidate the structural attributes of small molecules capable of agonism or antagonism or of elegantly switching between the two. The structural evolution of different chemotypes can provide the framework for the future development of endosomal TLR agonists and antagonists.

Synthesis and immunopharmacological evaluation of novel TLR7 agonistic triazole tethered imidazoquinolines

“…This variation in binding may be due to the chain length where in any substitution beyond butyl had an affinity to TLR8 as stated by Charles et al 23 This relative variation in activity may be due to the tolerating effect of TLR7 to modification at N1 and C2 which are apparently not required for activity, however, substitutions at these particular positions typically enhances the potency. 24 The C4 amine position which is required for activity was kept intact as any changes at this site would result in loss of activity. The other analogues had also elicited a TLR7 specific activity but relatively at higher concentrations than the standard.…”

Development, Optimization, and In Vivo Validation of New Imidazopyridine Chemotypes as Dual TLR7/TLR9 Antagonists through Activity-Directed Sequential Incorporation of Relevant Structural Subunits

“…The conceptual design of the compounds was influenced by our previous experience with the essential structural features and geometrical arrangements in different chemotypes such as benzoxazole, , oxoadenine, − imidazoquinoline, quinazoline, − and other cores. − To identify the minimal substitutions required to attain TLR7/9 antagonism, initially, 7–11 were prepared with small substituents at the C4′ and C2′ positions. The C2′ substitution was to impart obvious geometrical restrictions in the molecule.…”

“…TLR7 and TLR9 activation with their respective ligands lead to identical downstream signaling pathways initiated by the association with their adaptor protein Myd88 and culminating in the transcriptional activation of several inflammatory genes such as type I interferons or pro-inflammatory cytokines depending on the cell type and the endosomal localization of the ligands. , Dual antagonists targeting TLR7/9 serve as important tools to prevent undesirable activation and production of type I interferons in various inflammatory disease contexts. Antimalarial drugs chloroquine and hydroxychloroquine, with established inhibitory action on endosomal TLR activation, have been in clinical use against several major autoimmune diseases such as rheumatoid arthritis. , Several oligonucleotide TLR7/TLR9 antagonists such as IMO-8400, IMO-3100, and IMO-9200 have undergone evaluation in clinical trials to monitor their safety and efficacy in patients diagnosed with autoimmune disorders. − Pfizer initiated a clinical trial of a small molecule (CpG-52364) with a quinazoline core, but it failed to pass the phase I stage. ,, Several groups along with us have also previously demonstrated systematic development of potent TLR7 and TLR9 small-molecule antagonists based on benzoxazole, , quinazoline, − imidazoquinoline, and purine − scaffolds by employing different medicinal chemistry strategies. − Through agonist-to-antagonist strategy, we identified a chemical switch in the purine scaffold leading to a switch from TLR7 agonism to antagonism . An activity-guided strategy was employed for the development of selective TLR9 and dual TLR7/TLR9 antagonists in the quinazoline scaffold. , …”

Integration of Ligand-Based and Structure-Based Methods for the Design of Small-Molecule TLR7 Antagonists

“…The antimalarial agent hydroxychloroquine (HCQ), which operates as a nonselective endosomal TLR inhibitor, is widely utilized in the treatment of various autoimmune disorders [28]. Various researchers have reported molecules with quinazoline [29,30], benzoxazole [31][32][33], imidazopyridine [34,35], purine [36][37][38], and other varied scaffolds [39,40] that have been significantly investigated for the development of selective small-molecule TLR7 antagonists in several recent studies through empirical screenings and activity-guided strategies.…”