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

Autor: Jean-Pierre Sommadossi, Steven S. Good, Adel Moussa, Justin G. Julander, Abbie Weight, Kai Lin
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Male
Viral Diseases
Physiology
RC955-962
Biochemistry
Medical Conditions
Cricetinae
Arctic medicine. Tropical medicine
Chlorocebus aethiops
Metabolites
Medicine and Health Sciences
Prodrugs
Mammals
Vaccines
Guanosine
Yellow fever
Pro-Drugs
Eukaryota
Drugs
Prodrug
Body Fluids
Vaccination
Titer
Blood
Infectious Diseases
Physiological Parameters
Vertebrates
Hamsters
Female
Anatomy
Yellow fever virus
Public aspects of medicine
RA1-1270
Research Article
Infectious Disease Control
Viremia
Rodents
Microbiology
Antiviral Agents
Blood Plasma
Virus
Viral hemorrhagic fever
In vivo
Virology
Yellow Fever
medicine
Animals
Vero Cells
Pharmacology
Mesocricetus
business.industry
Body Weight
Organisms
Public Health
Environmental and Occupational Health
Biology and Life Sciences
Kidneys
Viral Vaccines
Renal System
medicine.disease
Metabolism
Amniotes
business
Zoology
Zdroj: PLoS Neglected Tropical Diseases, Vol 16, Iss 1, p e0009937 (2022)
PLoS Neglected Tropical Diseases
ISSN: 1935-2735
1935-2727
Popis: 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 vaccination 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 YFV in 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
Author summary Yellow fever virus (YFV) is transmitted by mosquitoes, and its infection can lead to a lethal viral hemorrhagic fever associated with liver damage. While an effective vaccine is available, in places where the vaccination rate is low, in the event of an unexpected outbreak, or where vaccination is not recommended individually, having an effective antiviral treatment is critical. We previously reported that the nucleotide analog prodrug AT-752 potently inhibited the YFV in cultured cells. Here we showed that in hamsters infected with YFV, oral treatment with 1000 mg/kg AT-752 for 7 days reduced the production of infectious virus particles in the blood, and decreased serum alanine aminotransferase, a marker of liver damage, to levels measured in uninfected animals. In addition, at 21 days after infection, 70–100% of the infected animals in the treatment groups survived compared to 0% in the untreated group. Moreover, the amount of the active metabolite formed from AT-752 was highest in the livers and kidneys of the treated animals, organs that are targeted by the virus. These results suggest that AT-752 is a promising compound to develop for the treatment of YFV infection.
Databáze: OpenAIRE
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