Targeting Organic Anion Transporter 3 with Probenecid as a Novel Anti-Influenza A Virus Strategy
| Autor: | Caleb White, Scott Johnson, Olivia Perwitasari, Paula Brooks, Ralph A. Tripp, Xiuzhen Yan, S. Mark Tompkins |
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| Rok vydání: | 2013 |
| Předmět: |
Small interfering RNA
Organic anion transporter 1 Gene Expression Drug resistance Organic Anion Transporters Sodium-Independent Pharmacology Virus Replication medicine.disease_cause Antiviral Agents Virus Cell Line Inhibitory Concentration 50 Influenza A Virus H1N1 Subtype Orthomyxoviridae Infections Influenza Human medicine Influenza A virus Humans Pharmacology (medical) RNA Small Interfering biology Probenecid Influenza A Virus H3N2 Subtype Drug Repositioning Uricosuric Agents Virology High-Throughput Screening Assays Drug repositioning Infectious Diseases Viral replication Host-Pathogen Interactions biology.protein Protein Binding medicine.drug |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 57:475-483 |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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