Targeting Toll-like receptors with small molecule agents

Abstract

Toll-like receptors (TLRs) are type I transmembrane proteins that are key regulators of both innate and adaptive immune responses. To protect the host from viral and bacterial threats, TLRs trigger a pro-inflammatory immune response by detecting pathogen and danger associated molecular patterns. Considerable evidence has accumulated to show that the dysregulation of TLR signaling contributes to the development and progression of numerous diseases. Therefore, TLRs are emerging as important drug discovery targets. Currently, there is great interest in the development of TLR small molecule modulators for interrogating TLR signaling and treating diseases caused by TLR signaling malfunctions. In this tutorial review, we will outline methods for the discovery of TLR small molecule modulators and the up-to-date progress in this field. Small molecules targeting TLRs not only provide an opportunity to identify promising drug candidates, but also unveil knowledge regarding TLR signaling pathways.

Fig. 1

High-resolution X-ray crystal structure of the human TLR4/MD-2/Eritoran complex. (A) Chemical structure of Eritoran. (B) Overall structure of the TLR4/hMD-2/Eritoran complex (PDB ID 2Z65, resolution 2.70 Å). (C) A close-up view of the binding site of Eritoran on the MD-2 surface. This figure is reprinted with permission.

Fig. 2

The small-molecule inhibitor, T5342126, identified through virtual screening. (A) The chemical structure of T5342126. (B) The TLR4/MD-2 complex as the target for T5342126. (C) T5342126 binds to the same site on the TLR4 surface that the MD-2 protein recognizes. This figure is reprinted with permission.

Fig. 3

Schematic of BB loop-derived peptides interacting with TLRs. BB loop-derived decoy peptides bind to the TLR TIR domain, preventing the TLR dimerization and its downstream signaling.