Masked oral prodrugs of toll-like receptor 7 agonists: a new approach for the treatment of infectious disease.
Toll-like receptor (TLR)7 is a pattern-recognition receptor that activates the innate immune response. Stimulation of TLR7 induces type I interferons, pro-inflammatory cytokines, the upregulation of co-stimulatory molecules and leads to the development of an adaptive immune response. Small-molecule TLR7 agonists with broad-spectrum antiviral activities in animal models have been identified. Such compounds have been examined clinically for a number of different infectious disease indications, leading to marketing approval of one of these agents, imiquimod, for the topical treatment of external genital and perianal papillomavirus infections. In contrast with topical and intravenous routes of administration, compounds delivered orally have exhibited poor tolerability at desired doses, with substantial adverse events associated with gastrointestinal toxicity. However, dosing with masked oral prodrugs of TLR7 agonists, such as ANA-975, limits the adverse events associated with the activation of responsive gastrointestinal immune tissue. As a consequence, the treatment of systemic diseases, such as chronic hepatitis C, can now be explored with orally administered TLR7 agonists.
Fletcher
Simon
S
Anadys Pharmaceuticals Inc, 3115 Merryfield Row, San Diego, CA 92121, USA.
Steffy
Kevin
K
Averett
Devron
D
D000284:Administration, Oral; D000634:Aminoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D006151:Guanosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology; D006801:Humans; D000077271:Imiquimod; D011355:Prodrugs / Q000008:administration & dosage*; D051199:Toll-Like Receptor 7 / Q000819:agonists* / Q000096:biosynthesis / Q000276:immunology
D000634:Aminoquinolines; D011355:Prodrugs; D051199:Toll-Like Receptor 7; D006151:Guanosine; C061136:isatoribine; D000077271:Imiquimod