Inhibition of influenza virus infections in mice by GS4104, an orally effective influenza virus neuraminidase inhibitor.
The carbocyclic transition state sialic acid analog GS4071 ([3R,4R,5S]-4-acetamido-5-amino-3-[1-ethylpropoxy]-1-cyclohexane-1 -carboxylic acid), a potent influenza virus neuraminidase inhibitor, was highly inhibitory to influenza A/NWS/33 (H1N1), A/Victoria/3/75 (H3N2), A/Shangdong/09/93 (H3N2) and B/Hong Kong/5/72 viruses in Madin Darby canine kidney (MDCK) cells. The 50% effective concentrations in these experiments ranged from 1.8 to 59.5 microM, with no cytotoxicity evident at 1000 microM, using inhibition of viral cytopathic effect determined visually and by neutral red dye uptake. The ethyl ester prodrug of GS4071, GS4104, administered by oral gavage (p.o.), had significant inhibitory effects on infections in mice induced by these viruses. Antiviral effects were seen as prevention of death, increase in mean day to death, inhibition of decline of arterial oxygen saturation, lessened lung consolidation and inhibition of infectious virus recovered from the lungs. No toxicity was seen in dosages up to 100 mg/kg/day (highest evaluated). Comparison experiments run versus the influenza A (H1N1) virus-induced infection using GS4104, GS4071 and the neuraminidase inhibitor zanamivir (GG167, 4-guanidino-Neu5Ac2en), all administered p.o., indicated a 10-fold or greater potency for inhibiting the infection by GS4104. The minimum effective dosage for GS4104 was 0.1 mg/kg/day, with the compound administered twice daily for 5 days beginning 4 h pre-virus exposure. Oral therapy with GS4104 could be delayed from 48 to at least 60 h after exposure of mice to influenza A (H1N1) virus and still render a significant antiviral effect, the time of delay being dependent on the viral challenge dose. Intranasal instillation of GS4071 and GG167 to mice infected with influenza virus was highly inhibitory to the infection, the minimum effective dosages to significantly prevent death being 0.01 mg/kg/day for GS4071 and 0.1 mg/kg/day for GG167. Caging of infected mice treated with 10 mg/kg/day of GS4104 with infected saline-treated animals did not transfer any influenza-inhibitory effect to the latter animals. These data provide strong evidence of the potential of orally administered GS4104 for treatment of influenza A and B virus infections in humans.
Sidwell
R W
RW
Institute for Antiviral Research, Utah State University, Logan 84322-5600, USA. Rsidwell@cc.usu.edu
Huffman
J H
JH
Barnard
D L
DL
Bailey
K W
KW
Wong
M H
MH
Morrison
A
A
Syndergaard
T
T
Kim
C U
CU
D000081:Acetamides / Q000494:pharmacology / Q000627:therapeutic use; D000281:Administration, Intranasal; D000284:Administration, Oral; D000588:Amines / Q000627:therapeutic use*; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D002460:Cell Line; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D006146:Guanidines; D006801:Humans; D009980:Influenza A virus / Q000187:drug effects*; D009981:Influenza B virus / Q000187:drug effects; D007251:Influenza, Human / Q000188:drug therapy*; D008171:Lung Diseases / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D015394:Molecular Structure; D009439:Neuraminidase / Q000037:antagonists & inhibitors*; D053139:Oseltamivir; D011714:Pyrans; D012254:Ribavirin / Q000627:therapeutic use; D012794:Sialic Acids / Q000627:therapeutic use; D053243:Zanamivir
D000081:Acetamides; D000588:Amines; D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D006146:Guanidines; D011714:Pyrans; D012794:Sialic Acids; D053139:Oseltamivir; D012254:Ribavirin; D009439:Neuraminidase; D053243:Zanamivir