title: Optimizing celgosivir therapy in mouse models of dengue virus infection of serotypes 1 and 2: The search for a window for potential therapeutic efficacy.
abstract: Although the antiviral drug celgosivir, an α-glucosidase I inhibitor, is highly protective when given twice daily to AG129 mice infected with dengue virus, a similar regimen of twice daily dosing did not significantly reduce serum viral loads in patients in a recent clinical trial. This failure presumably might reflect the initiation of treatment when patients were already viremic. To better mimic the clinical setting, we used viruses isolated from patients to develop new mouse models of DENV1 and DENV2 infection and employed the models to test the twice daily treatment, begun either on the day of infection or on the third day post-infection, when the mice had peak of viremia. We found that, although the treatment started on day 0 was effective on viral load reduction, it provided no benefit when begun on day 3, indicating that in vivo antiviral efficacy becomes less prominent once viremia reaches the peak level. To determine if the therapeutic regimen in humans could be improved, we tested regimen of four-times daily treatment and found that the treatment significantly reduced viremia, suggesting that a similar regimen may be effective in a human clinical trial. A new clinical trial to investigate an altered dosing regimen has been approved (NCT02569827).
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8-College Road, Singapore 169857.
authors.forename: Satoru
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8-College Road, Singapore 169857.
authors.forename: Kitti Wing-Ki
authors.initials: KW
authors.lastname: Chan
authors.affiliation: 60° Pharmaceuticals LLC, Washington, DC, 20036, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Dow
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8-College Road, Singapore 169857.
authors.forename: Eng Eong
authors.initials: EE
authors.lastname: Ooi
authors.affiliation: Department of Infectious Diseases, Singapore General Hospital, 20 College Road, Singapore 16985.
authors.forename: Jenny G
authors.initials: JG
authors.lastname: Low
authors.affiliation: Program in Emerging Infectious Diseases, Duke-NUS Graduate Medical School, 8-College Road, Singapore 169857. Electronic address: subhash.vasudevan@duke-nus.edu.sg.
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage; D002460:Cell Line; D002522:Chlorocebus aethiops; D006224:Cricetinae; D016207:Cytokines / Q000097:blood; D003715:Dengue / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D003716:Dengue Virus / Q000145:classification / Q000302:isolation & purification*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D006801:Humans; D066298:In Vitro Techniques; D007212:Indolizines / Q000008:administration & dosage*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D065288:Serogroup; D014709:Vero Cells; D019562:Viral Load / Q000187:drug effects; D014766:Viremia / Q000188:drug therapy / Q000821:virology; D000520:alpha-Glucosidases / Q000378:metabolism; D054836:Indolizidines
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004791:Enzyme Inhibitors; D007212:Indolizines; D000520:alpha-Glucosidases; C070715:celgosivir; D054836:Indolizidines; C042059:glucosidase I
keywords: AG129 mouse model; Antiviral; Celgosivir; Dengue virus; Viremia reduction