AT-752, a double prodrug of a guanosine nucleotide analog, inhibits yellow fever virus in a hamster model

by Kai Lin, Steven S. Good, Justin G. Julander, Abbie E. Weight, Adel Moussa, Jean-Pierre Sommadossi Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing a viral hemorrhagic fever associated with high mortality rates. While an effective vaccine is available, having an effective antiviral against YFV is critical against unexpected outbreaks, or when vaccinatio n is not recommended. We have previously identified AT-281, the free base of AT-752, an orally available double prodrug of a guanosine nucleotide analog, as a potent inhibitor of YFVin vitro, with a 50% effective concentration (EC50) of 0.31 μM. In hamsters infected with YFV (Jimenez strain), viremia rose about 4 log10-fold and serum alanine aminotransferase (ALT) 2-fold compared to sham-infected animals. Treatment with 1000 mg/kg AT-752 for 7 days, initiated 4 h prior to viral challenge, reduced viremia to below the limit of detection by day 4 post infection (pi) and returned ALT to normal levels by day 6 pi. When treatment with AT-752 was initiated 2 days pi, the virus titer and ALT dropped>2 log10 and 53% by day 4 and 6 pi, respectively. In addition, at 21 days pi, 70 –100% of the infected animals in the treatment groups survived compared to 0% of the untreated group (p
Source: PLoS Neglected Tropical Diseases - Category: Tropical Medicine Authors: Source Type: research