Recent trends in the development of Toll-like receptor 7/8-targeting therapeutics

ABSTRACT

Introduction: Toll-like receptor (TLR) 7 and TLR8 are functionally localized to endosomes and recognize specific RNA sequences. They play crucial roles in initiating innate and adaptive immune responses. TLR7/8 activation protects the host against invading pathogens and enhances immune responses. In contrast, sustained TLR7/8 signaling leads to immune overreaction. Therefore, agonists or antagonists targeting TLR7/8 signaling are favorable drug candidates for the treatment of immune disorders.

Areas covered: Basic knowledge about TLR7 and TLR8 and their signaling pathways are briefly reviewed. Various therapeutic agents have been designed to activate or antagonize TLR7/8 signaling pathways, and their safety and efficacy for the treatment of multiple diseases have been investigated in preclinical animal models and clinical trials. TLR7/8 agonists exhibit potent antiviral activity and regulate anti-tumor immune responses. TLR7 agonists have also been used as adjuvants to improve vaccine immunogenicity and generate greater seroprotection. TLR7/8 antagonists are promising candidates for the treatment of autoimmune and inflammatory diseases.

Expert opinion: TLR7/8 pathways are favorable targets for immunological therapies. Future research should concentrate on the optimization of drug safety, efficiency, and specificity. Detailed mechanistic studies will contribute to the development of TLR7/8 immunomodulators and novel therapeutic strategies.

KEYWORDS:

• Agonist
• antagonist
• clinical trial
• innate immunity
• toll-like receptor 7/8

Highlight box

• Toll-like receptor (TLR) 7 and TLR8 are closely related members of the TLR family. They are sensors of single-stranded ribonucleic acids from endosomal compartments and nucleoside-based molecules.

• TLR7 activates plasmacytoid dendritic cells and leads to the production of type I interferon. TLR8 is mainly expressed in myeloid dendritic cells, monocytes, and macrophages and induces secretion of proinflammatory cytokines.

• TLR7 and TLR8 are important regulators of innate and adaptive immune responses, therefore representing potential targets for immune therapy.

• TLR7/8 agonists have been evaluated on various diseases associated with deficient immune responses, such as chronic viral infections, cancers, and allergic diseases, and in vaccine studies. Safety and efficacy have been demonstrated in several studies.

• TLR7/8 antagonists have mainly been studied in autoimmune and inflammatory diseases. Such agents were safe and significantly downregulated in the expression of inflammation-related cytokines.

Acknowledgments

The authors acknowledge Dr. Yin Wu for his assistance in data collection.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

One referee declares that they work on the development of therapeutic TLR7/8 inhibitors and activators and have provisional and PCT patent applications on the topic. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work is supported by the National Natural Science Foundation of China [81702009].