The prophylactic and therapeutic activity of a broadly active ribonucleoside analog in a murine model of intranasal venezuelan equine encephalitis virus infection

Therapeutically administered ribonucleoside analogue MK-4482/EIDD-2801 blocks SARS-CoV-2 transmission in ferrets

“…Closely resembling our previous experience with influenza therapy 4,10 , MK-4482/EIDD-2801 was well tolerated and orally efficacious against SARS-CoV-2, reducing the upper respiratory virus load to below the detection level within 24 h of the first drug administration when therapy was initiated after the onset of virus shedding and by nearly two orders of magnitude when first administered at the peak of virus replication. Similarly, viral genetic material was undetectable in the gastrointestinal samples of the treated animals, which is consistent with previous observations of a sustained presence of the biologically active triphosphate form of NHC in all soft tissue, except liver, in different species 4,12,24 .…”

Therapeutic MK-4482/EIDD-2801 Blocks SARS-CoV-2 Transmission in Ferrets

“…Closely resembling our prior experience with influenza therapy 4 , 6 , MK-4482/EIDD-2801 was well tolerated and orally efficacious against SARS-CoV-2, reducing upper respiratory virus load below detection level within 24 hours of first drug administration when therapy was initiated after the onset of virus shedding, and by nearly two orders of magnitude when first administered at the peak of virus replication. Viral genetic material in gastrointestinal samples was likewise undetectable in treated animals, which is consistent with previous observations of sustained presence of the biologically active triphosphate form of NHC in all soft tissue but liver in different species 4 , 8 , 29 .…”

“…By coincidence, 5 mg/kg is close to the lowest efficacious dose of MK-4482/EIDD-2801 against seasonal and pandemic influenza viruses in ferrets4,6 , underscoring the high broad-spectrum antiviral potential of the drug.Closely resembling our prior experience with influenza therapy4,6 , MK-4482/EIDD-2801 was well tolerated and orally efficacious against SARS-CoV-2, reducing upper respiratory virus load below detection level within 24 hours of first drug administration when therapy was initiated after the onset of virus shedding, and by nearly two orders of magnitude when first administered at the peak of virus replication. Viral genetic material in gastrointestinal samples was likewise undetectable in treated animals, which is consistent with previous observations of sustained presence of the biologically active triphosphate form of NHC in all soft tissue but liver in different species4,8,29 .Importantly, treatment suppressed all transmission to untreated direct contacts, despite prolonged direct proximity of source and contact animals and detectable virus shedding from source animals at the beginning of the co-housing phase. This complete transmission block may indicate a bottom threshold of shed SARS-CoV-2 load for successful spread.…”

Analysis of the Potential for N 4 -Hydroxycytidine To Inhibit Mitochondrial Replication and Function

“…at 200 mg/kg/day, despite the fact that plasma levels of NHC were expected to be above 10 M at any time throughout the treatment course (26). It has been shown that NHC was efficiently anabolized to the triphosphate form in primary hepatocytes and in animal organs in vivo (16,26,31). The decrease in quantity of mitochondrial protein or the potential decrease of functional activity of mitochondrial proteins may result in less production of ATP by the mitochondria even if the mitochondrial number has not changed.…”