Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Targeting the Organic Anion Transporter-3 (OAT3) with Probenecid as a Novel Anti-Influenza A Virus Strategy
Olivia Perwitasari, Xiuzhen Yan, Scott Johnson, Caleb White, Paula Brooks, S. Mark Tompkins and Ralph A. Tripp#
Author Affiliations: University of Georgia, College of Veterinary Medicine, Dept. Infectious Diseases, 111 Carlton Street, Athens, GA 30302
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 was identified to target OAT3, and shown to be effective in limiting influenza A virus infection in vitro (IC<SUB>50</SUB> of 5.0?10<SUP>-5</SUP> to 5.0?10<SUP>-4</SUP> 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.
FOOTNOTES
#Corresponding author: Ralph A. Tripp, Department of Infectious Diseases, Animal Health Research Center, University of Georgia, 111 Carlton Street, Athens, GA 30602; (t): 706-542-4312; (f): 706-583-0176; (e): ratripp@uga.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
-Author Affiliations: University of Georgia, College of Veterinary Medicine, Dept. Infectious Diseases, 111 Carlton Street, Athens, GA 30302
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 was identified to target OAT3, and shown to be effective in limiting influenza A virus infection in vitro (IC<SUB>50</SUB> of 5.0?10<SUP>-5</SUP> to 5.0?10<SUP>-4</SUP> 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.
FOOTNOTES
#Corresponding author: Ralph A. Tripp, Department of Infectious Diseases, Animal Health Research Center, University of Georgia, 111 Carlton Street, Athens, GA 30602; (t): 706-542-4312; (f): 706-583-0176; (e): ratripp@uga.edu
Copyright ? 2012, American Society for Microbiology. All Rights Reserved.
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