Recent progress in the development of Toll-like receptor (TLR) antagonists

ABSTRACT

Introduction: Pattern recognition receptors (PRRs) of the innate immune system mediate and control the activation and progression of adaptive immunity. Toll-like receptors (TLRs) are the most notable of the PRRs: they play crucial roles in protecting the host body against invading pathogens or endogenously released hazardous molecules. Sustained TLR signaling even after the clearance of pathogens or failure to distinguish between ‘self’ and ‘non-self’ molecules can cause inflammatory disorders, autoimmune diseases, and cancer.

Areas covered: This review focuses on recently developed therapeutic agents with TLR-antagonistic activities.

Expert opinion: In recent years, several research institutes and pharmaceutical companies have achieved fundamental successes in inhibiting or reducing TLR signaling and associated effector mechanisms by using novel inhibitors. These inhibitory molecules include antibodies against TLRs, TLR-derived transmembrane (TM) peptides, bacterial-secreted proteins, and natural or synthetic small molecules, peptides, and proteins. Antagonist developers generally target the TLR ectodomain to block receptor activation. The TM and cytosolic Toll/IL-1 receptor domains also have regions that should be explored for the design of peptide-based and small molecule blocking agents. A number of preclinical and clinical breakthroughs may result in the availability of improved TLR immunomodulatory drugs to address important unmet medical needs.

KEYWORDS:

• Toll-like receptor
• innate immunity
• antagonist
• patent
• clinical trial

Article highlights

• Toll-like receptors (TLRs) are important regulators of innate and adaptive immune responses.

• Aberrant TLR signaling has been implicated in several autoimmune and inflammatory diseases, including cancer.

• Antagonists developed for downmodulating overactive TLR signaling include small molecules, aptamers, oligonucleotides, peptides, proteins, and antibodies.

• In addition to the extracellular domain, the transmembrane and Toll/IL-1 receptor domains have been explored to develop more effective TLR blockers.

• Some antagonists interfere with intracellular adaptors, alter the pH of endosomal compartments, or neutralize oligonucleotide agonists through weak interactions.

• Some antagonists have either completed or are in advanced phase III clinical trials and have demonstrated safety and efficacy.

This box summarizes key points contained in the article.

Declaration of interests

This work was supported by the Mid-Career Researcher Program through the National Research Foundation of Korea, funded by the Ministry of Education, Science, and Technology (NRF-2015R1A2A2A09001059), and by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (HI14C1992). This work was also partially supported by a grant from the Priority Research Centers Program (NRF 2012-0006687). 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.