Recent Advances on Small-Molecule Antagonists Targeting TLR7

Abstract

Toll-like receptor 7 (TLR7) is a class of pattern recognition receptors (PRRs) recognizing the pathogen-associated elements and damage and as such is a major player in the innate immune system. TLR7 triggers the release of pro-inflammatory cytokines or type-I interferons (IFN), which is essential for immunoregulation. Increasing reports also highlight that the abnormal activation of endosomal TLR7 is implicated in various immune-related diseases, carcinogenesis as well as the proliferation of human immunodeficiency virus (HIV). Hence, the design and development of potent and selective TLR7 antagonists based on small molecules or oligonucleotides may offer new tools for the prevention and management of such diseases. In this review, we offer an updated overview of the main structural features and therapeutic potential of small-molecule antagonists of TLR7. Various heterocyclic scaffolds targeting TLR7 binding sites are presented: pyrazoloquinoxaline, quinazoline, purine, imidazopyridine, pyridone, benzanilide, pyrazolopyrimidine/pyridine, benzoxazole, indazole, indole, and quinoline. Additionally, their structure-activity relationships (SAR) studies associated with biological activities and protein binding modes are introduced.

Structure–Activity Relationships toward the Identification of a High-Potency Selective Human Toll-like Receptor-7 Agonist

“…When an agonist ligand binds to the TLR7 or -8 homodimer, the two C-terminal domains move within 23 Å of each other, and this expedites the dimerization of the TLR domains, which initiates the downstream signaling cascade and immune cell activation. , To better understand how the BBIQ derivatives may bind to TLR7 and/or TLR8 and which interactions are responsible for achieving TLR7 specificity, we performed studies of docking of the synthesized compounds to characterize the interactions of the ligands with the binding pocket. We used the three-dimensional structure of monkey TLR7 complexed with loxoribine and polyU (PDB entry 5GMG) due to its relatively simple composition with only two chains (A and B), thereby minimizing distortion upon removal of additional components such as water and ions. , A TLR8 structure bound to the agonist selgantolimod (PDB entry 6WML) was used for the TLR8 studies. , …”

“…We used the threedimensional structure of monkey TLR7 complexed with loxoribine and polyU (PDB entry 5GMG) due to its relatively simple composition with only two chains (A and B), thereby minimizing distortion upon removal of additional components such as water and ions. 44,45 A TLR8 structure bound to the agonist selgantolimod (PDB entry 6WML) was used for the TLR8 studies. 46,47 Predicted conformations of resiquimod and 23 docked to the ligand binding site of human TLR7 and TLR8 are shown in Figure 6.…”

Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus

“…Furthermore, although the structural location of UNC93B1 T314A presents a logical mechanism to impact TLR7, the molecular effect of UNC93B1 V117L is not yet clear. Mechanistic insight into this process will be extremely useful, and potentially clinically actionable in the future as TLR7 inhibitors are being developed 25 .…”

Structural Optimization and Biological Evaluation of Isoxazolo[5,4-d]pyrimidines as Selective Toll-Like Receptor 7 Agonists

“…Upon binding of an endogenous ligand or a small synthetic nucleoside analog, TLR 7 dimerizes and subsequent conformational changes trigger the myeloid differentiation primary response protein 88 (MyD88) signaling cascade. This leads to the release and translocation of activated NF-κB or AP-1 to the nucleus, where the expression of pro-inflammatory cytokines and type I interferons is induced. − It was shown previously that upregulated or downregulated TLR7 signaling is involved in the development and progression of numerous diseases, including chronic inflammatory and infectious diseases, autoimmune diseases, and cancer. − However, the use of TLR7 agonists in the treatment of these diseases is still in the research phase, so further clinical studies are needed to fully understand their role and efficacy.…”

“… 5 − 7 It was shown previously that upregulated or downregulated TLR7 signaling is involved in the development and progression of numerous diseases, including chronic inflammatory and infectious diseases, autoimmune diseases, and cancer. 8 − 10 However, the use of TLR7 agonists in the treatment of these diseases is still in the research phase, so further clinical studies are needed to fully understand their role and efficacy.…”