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: Olivia Perwitasari, Xiuzhen Yan, Scott Johnson, Caleb White, Paula Brooks, S Mark Tompkins, Ralph A Tripp
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 57 Issue 1 Pg. 475-83 (Jan 2013) ISSN: 1098-6596 [Electronic] United States
• PMID: 23129053 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antiviral Agents
• Organic Anion Transporters, Sodium-Independent
• RNA, Small Interfering
• Uricosuric Agents
• organic anion transport protein 3
• Probenecid

Topics

• Antiviral Agents (pharmacology)
• Cell Line
• Drug Repositioning
• Gene Expression
• High-Throughput Screening Assays
• Host-Pathogen Interactions
• Humans
• Influenza A Virus, H1N1 Subtype (drug effects, physiology)
• Influenza A Virus, H3N2 Subtype (drug effects, physiology)
• Influenza, Human (drug therapy, virology)
• Inhibitory Concentration 50
• Organic Anion Transporters, Sodium-Independent (antagonists & inhibitors, genetics, metabolism)
• Orthomyxoviridae Infections (drug therapy, virology)
• Probenecid (pharmacology)
• Protein Binding
• RNA, Small Interfering (genetics)
• Uricosuric Agents (pharmacology)
• Virus Replication (drug effects)