title: Targeting organic anion transporter 3 with probenecid as a novel anti-influenza a virus strategy.
abstract: Influenza A virus infection is a major global health concern causing significant mortality, morbidity, and economic loss. Antiviral chemotherapeutics that target influenza A virus are available; however, rapid emergence of drug-resistant strains has been reported. Consequently, there is a burgeoning need to identify novel anti-influenza A drugs, particularly those that target host gene products required for virus replication, to reduce the likelihood of drug resistance. In this study, a small interfering RNA (siRNA) screen was performed to identify host druggable gene targets for anti-influenza A virus therapy. The host organic anion transporter-3 gene (OAT3), a member of the SLC22 family of transporters, was validated as being required to support influenza A virus replication. Probenecid, a prototypical uricosuric agent and chemical inhibitor of organic anion transporters known to target OAT3, was shown to be effective in limiting influenza A virus infection in vitro (50% inhibitory concentration [IC(50)] of 5.0 × 10(-5) to 5.0 × 10(-4) μM; P < 0.005) and in vivo (P < 0.05). Probenecid is widely used for treatment of gout and related hyperuricemic disorders, has been extensively studied for pharmacokinetics and safety, and represents an excellent candidate for drug repositioning as a novel anti-influenza A chemotherapeutic.
authors.affiliation: University of Georgia, College of Veterinary Medicine, Department of Infectious Diseases, Athens, Georgia, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Perwitasari
authors.forename: Xiuzhen
authors.initials: X
authors.lastname: Yan
authors.forename: Scott
authors.initials: S
authors.lastname: Johnson
authors.forename: Caleb
authors.initials: C
authors.lastname: White
authors.forename: Paula
authors.initials: P
authors.lastname: Brooks
authors.forename: S Mark
authors.initials: SM
authors.lastname: Tompkins
authors.forename: Ralph A
authors.initials: RA
authors.lastname: Tripp
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D058492:Drug Repositioning; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D054884:Host-Pathogen Interactions; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000821:virology; D020128:Inhibitory Concentration 50; D029362:Organic Anion Transporters, Sodium-Independent / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D011339:Probenecid / Q000494:pharmacology*; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D014528:Uricosuric Agents / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D029362:Organic Anion Transporters, Sodium-Independent; D034741:RNA, Small Interfering; D014528:Uricosuric Agents; C114338:organic anion transport protein 3; D011339:Probenecid