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.

Keywords: TLR7; antagonists; heterocycle; innate immunity.

Figure 1

Structure and signaling pathways of the toll-like receptor 7 (TLR7): (a) Schematic representation of TLR7. The N-terminal ectodomain (ECD) locates in the endosome. The transmembrane helix consists of an α-helix across the endosomal membrane. The details of the structure of toll/interleukin-1 receptor (TIR) domain are not illustrated due to the lack of data for TLR7. Data are from reference [23] (PDB ID: 7CYN). (b) Front view of the ECD dimer. The cleaved Z-loop and a disulfide bridge between Cys98 and Cys475 are shown in cyan and yellow, respectively. The binding site of small molecules and synthetized oligonucleotides are illustrated in red and blue, respectively. Data are from reference [24] (PDB ID: 5GMG). (c) TLR7-mediated MyD88-dependent signaling pathways. Firstly, the recognition between small-molecule ligands or ssRNA and TLR7 allows to initiate downstream signaling. MyD88 then forms the myddosome with IRAK4, which phosphorylates and releases IRAK1. After that, TRAF6 is auto-ubiquitinated and activates TAK1. TAK1 forms a complex with TAB1/2/3. Finally, translocation of NF-κB and activation of MAPK signaling pathway generates innate immune responses that lead to the production of pro-inflammatory cytokines and IFNs.

Figure 2

Imiquimod analogs and quinazoline derivatives.

Figure 3

Structure-activities relation (SAR) studies and chemical structures for purine derivatives.

Figure 4

SAR studies on imidazopyridine derivatives.

Figure 5

SAR studies with pyridone derivatives.

Figure 6

Structures of benzanilide-based ligands and SAR studies of pyrazolopyrimidine/pyridine derivatives.

Figure 7

Benzoxazole and indazole derivatives.

Figure 8

Indole and quinoline TLR7 antagonist derivatives.