TLR4 biased small molecule modulators

Cong Lin; Hongshuang Wang; Miyuan Zhang; Sanam Mustafa; Yibo Wang; Hongyuan Li; Hang Yin; Mark R Hutchinson; Xiaohui Wang

doi:10.1016/j.pharmthera.2021.107918

TLR4 biased small molecule modulators

Pharmacol Ther. 2021 Dec:228:107918. doi: 10.1016/j.pharmthera.2021.107918. Epub 2021 Jun 23.

Authors

Cong Lin¹, Hongshuang Wang², Miyuan Zhang³, Sanam Mustafa⁴, Yibo Wang², Hongyuan Li², Hang Yin⁵, Mark R Hutchinson⁶, Xiaohui Wang⁷

Affiliations

¹ Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, Jiangsu 210023, China.
² Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China.
³ Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China.
⁴ Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia 5000, Australia.
⁵ School of Pharmaceutical Sciences, Tsinghua University-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100082, China.
⁶ Discipline of Physiology, Adelaide Medical School, University of Adelaide, South Australia, Australia; ARC Centre of Excellence for Nanoscale Biophotonics, University of Adelaide, South Australia 5000, Australia. Electronic address: mark.hutchinson@adelaide.edu.au.
⁷ Laboratory of Chemical Biology, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Applied Chemistry and Engineering, University of Science and Technology of China, Hefei 230026, China. Electronic address: xiaohui.wang@ciac.ac.cn.

PMID: 34171331
DOI: 10.1016/j.pharmthera.2021.107918

Abstract

Biased pharmacological modulators provide potential therapeutic benefits, including greater pharmacodynamic specificity, increased efficiency and reduced adverse effects. Therefore, the identification of such modulators as drug candidates is highly desirable. Currently, attention was mainly paid to biased signaling modulators targeting G protein-coupled receptors (GPCRs). The biased signaling modulation of non-GPCR receptors has yet to be exploited. Toll-like receptor 4 (TLR4) is one such non-GPCR receptor, which involves MyD88-dependent and TRIF-dependent signaling pathways. Moreover, the dysregulation of TLR4 contributes to numerous diseases, which highlights the importance of biased modulator development targeting TLR4. In this review, we aim to provide an overview of the recent progress in the discovery of biased modulators of TLR4. The challenges and methods for the discovery of TLR4 biased modulators are also outlined. Small molecules biasedly modulating the TLR4 signaling axis not only provide probes to fine-tune receptor conformation and signaling but also provide an opportunity to identify promising drug candidates. The discovery of biased modulators of TLR4 would provide insight for the future development of biased modulators for other non-GPCR receptors.

Keywords: Biased ligand; Biased signaling; Drug discovery; MyD88; TRIF; Toll-like receptor 4.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Drug Discovery
Humans
Signal Transduction / drug effects
Toll-Like Receptor 4* / drug effects
Toll-Like Receptor 4* / metabolism

Substances

Toll-Like Receptor 4