Identifying the inhibition of TIR proteins involved in TLR signalling as an anti-inflammatory strategy

Abstract

Toll/IL1 receptor (TIR) adaptor proteins continue to be an integral part of Toll-like receptors’ (TLR) signalling involved in inflammation. Signalling is likely to be initiated by these TIR adaptors when they are recruited to a TIR–TIR interface formed by TLR dimerization. Among these, myeloid differentiation factor-88 (MyD88), MyD88 adapter-like protein (Mal), TIR domain-containing adaptor protein inducing interferon-β (TRIF) and TRIF-related adaptor molecule (TRAM) play pivotal roles at many steps in the signalling events leading to inflammation. The presence of the conserved BB loop residues in the TIR domain of all these important adaptor proteins make them possible targets for inhibition by synthetic compounds. We have designed compounds based on an already known MyD88 TIR dimerization inhibitor, T6167923, which binds well not only to the original target but also to the TIR domains of Mal, TRIF and TRAM. The designed inhibitors are based on modifications of the bromophenyl-sulphonyl-thiophenyl-piperazine-carboxamide series of compounds. We have further suggested modifications in these high-affinity compounds for efficient absorption inside the body. Further, a pharmacophore model highlighting important structural interaction features has been developed. The screened compounds are better in binding to the TIR proteins then the parent compound and hence are good starting points for multi-TIR inhibition.

Keywords:

• TIR domain
• TLR
• inflammation
• synthetic compounds
• MyD88
• Mal
• TRIF
• TRAM

Acknowledgments

This work was supported by the Department of Biotechnology sponsored Ramalingaswami Fellowship (BT/RLF/ Re-entry/26/2013) and Department of Science and Technology (DST) funded Early Career Reserch Grant (ECR/2016/000852) to MSB and the Science and Engineering Research Board (SERB) Young Scientists Start-Up Research Grant under grant number YSS/2015/001279 to US. The authors also gratefully acknowledge the Indian Institute of Technology Indore for providing facilities and other support.