- Warfield, Kelly L;
- Plummer, Emily M;
- Sayce, Andrew C;
- Alonzi, Dominic S;
- Tang, William;
- Tyrrell, Beatrice E;
- Hill, Michelle L;
- Caputo, Alessandro T;
- Killingbeck, Sarah S;
- Beatty, P Robert;
- Harris, Eva;
- Iwaki, Ren;
- Kinami, Kyoko;
- Ide, Daisuke;
- Kiappes, JL;
- Kato, Atsushi;
- Buck, Michael D;
- King, Kevin;
- Eddy, William;
- Khaliq, Mansoora;
- Sampath, Aruna;
- Treston, Anthony M;
- Dwek, Raymond A;
- Enterlein, Sven G;
- Miller, Joanna L;
- Zitzmann, Nicole;
- Ramstedt, Urban;
- Shresta, Sujan
The antiviral activity of UV-4 was previously demonstrated against dengue virus serotype 2 (DENV2) in multiple mouse models. Herein, step-wise minimal effective dose and therapeutic window of efficacy studies of UV-4B (UV-4 hydrochloride salt) were conducted in an antibody-dependent enhancement (ADE) mouse model of severe DENV2 infection in AG129 mice lacking types I and II interferon receptors. Significant survival benefit was demonstrated with 10-20 mg/kg of UV-4B administered thrice daily (TID) for seven days with initiation of treatment up to 48 h after infection. UV-4B also reduced infectious virus production in in vitro antiviral activity assays against all four DENV serotypes, including clinical isolates. A set of purified enzyme, in vitro, and in vivo studies demonstrated that inhibition of endoplasmic reticulum (ER) α-glucosidases and not the glycosphingolipid pathway appears to be responsible for the antiviral activity of UV-4B against DENV. Along with a comprehensive safety package, these and previously published data provided support for an Investigational New Drug (IND) filing and Phases 1 and 2 clinical trials for UV-4B with an indication of acute dengue disease.