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

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.