TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders.

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Sun S, Rao NL, Venable J, Thurmond R, Karlsson L

TLR7/9 antagonists as therapeutics for immune-mediated inflammatory disorders.

Inflamm Allergy Drug Targets. 2007 Dec;6(4):223-35.

PubMed ID

18220957 [ View in PubMed

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Abstract

There is an increasing interest in ligands of nucleic acid-sensing Toll-like receptors (TLR), especially TLR7 and TLR9, for pharmacological intervention in various diseases. The TLR7 agonist imiquimod is currently used as a topical treatment for genital warts caused by human papillomavirus (HPV), actinic keratosis (AK) and superficial basal cell carcinoma. Oligodeoxynucleotides (ODN) TLR9 agonists are currently in clinical trials for use in lung cancer, as anti-viral therapy, as adjuvants and as immune modulators in asthma and allergies. TLR7/9 antagonists, such as the anti-malaria drugs chloroquine, hydroxychloroquine and quinacrine, have been used since the 1950s to treat immune-mediated inflammatory disorders (IMID) such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and Sjogren's syndrome. However, the use of these anti-malarials in IMID is limited due to the side effects or suboptimal efficacy. Pre-clinical animal models as well as genetic linkage studies have indicated that TLR7/9 play a pivotal role in the aforementioned as well as other IMID such as multiple sclerosis (MS), inflammatory bowl disease (IBD)/colitis and psoriasis. Recent evidence has suggested that selective, specific antagonists for TLR7 and/or 9 might be more beneficial in certain diseases, such as SLE. Thus, the use of suppressive ODN or novel small molecule TLR7/9 inhibitors with a larger safety window and differentiated selectivity may potentially have significant clinical utility in these IMID. Herein, we review efforts to develop novel TLR7/9 antagonists and the rationale for the use of such therapeutics in a variety of IMID.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Hydroxychloroquine	Toll-like receptor 7	Protein	Humans	Yes	Antagonist	Details
Hydroxychloroquine	Toll-like receptor 9	Protein	Humans	Yes	Antagonist	Details