Inhibitors of Toll-Like Receptor 4 (TLR4) – Homodimerization: Nipping in the Bud

Toll-like receptors (TLRs) play a key role in sensing microbial components and hence in eliciting innate immune responses. Lipopolysaccharide (LPS)-induced dimerization of TLR4 is a prerequisite for the activation of downstream signaling cascade including nuclear factor-kappa B (NF-κB). Hence, the receptor dimerization is a primary regulatory event in the activation of TLRsignaling which could be targeted to inhibit the inflammatory pathway. Many small organic molecules of both natural and synthetic origin have been discovered in the past few years. In this brief review, we throw light on a common structural motif of an α,β-unsaturated carbonyl group utilized by various natural and synthetic inhibitors of TLR-4 signaling. These inhibitors disrupt the disulphide bonds present between the cysteine residues at the extracellular domain of TLR4 which eventually inhibits its dimerization. This brief review focusses on how the present understanding about the mode of inhibition of these few but important inhibitors could be well utilized for further drug discovery and development. Saqib U, Baig MS (2016) Inhibitors of Toll-Like Receptor 4 (TLR4) – Homodimerization: Nipping in the Bud. Int J Drug Dev & Res 8: 020-023 Volume 8(3): 020-023 (2016)-021 Int J Drug Dev & Res ISSN: 0975-9344 Cinnamaldehyde