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A new oral antiviral with broad-spectrum effectiveness against many viruses, including coronaviruses: NHC (N-hydroxycytidine isopropyl ester): hope to treat COVID-19

2020-05-31

Coronavirus studies by Engin Akyurt via pixabay.com

A new article gives additional evidence that NHC may be useful against novel coronaviruses in humans.  Previously, in October 2019, the drug was tested against influenza with good results and the results published in Science Translational Medicine.  The new article adds testing against Middle Eastern Respiratory Virus (MERS)

From a Science Translational Medicine article posted April 29:

In mice infected with SARS-CoV or MERS-CoV, both prophylactic and therapeutic administration of EIDD-2801, an orally bioavailable NHC prodrug (β-D-N4-hydroxycytidine-5′-isopropyl ester), improved pulmonary function and reduced virus titer and body weight loss. Decreased MERS-CoV yields in vitro and in vivo were associated with increased transition mutation frequency in viral, but not host cell RNA, supporting a mechanism of lethal mutagenesis in CoV. The potency of NHC/EIDD-2801 against multiple CoVs and oral bioavailability highlights its potential utility as an effective antiviral against SARS-CoV-2 and other future zoonotic CoVs.

NHC (β-D-N4-hydroxycytidine-5′-isopropyl ester) is an orally available prodrug which hydrolyzes to the active form, N-hydroxycytidine.  It has been previously investigated against influenza virus.  This study and review looks at NHC’s effects on SARS-CoV-2, MERS-CoV, SARS-CoV, and related zoonotic group 2b or 2c bat-CoVs.  It works by incorporating into the growing RNA chain that is produced by the viral RNA-dependent RNA polymerase which creates new virus RNA (the genome of the infectious virus.)  Once incorporated, it leads to mutations which make the new RNA highly abnormal and no longer infectious.

This mechanism is related to the effect of remdesivir (RDV), which is also incorporated into the growing RNA chain but leads to immediate termination of the chain and its inability to become a complete virus genome.  NHC is also effective against mutations of coronavirus which are resistant to the effect of RDV.

Mice are resistant to SARS-COV-2 due to differences in the mouse cell surface receptor for ACE-2.  Therefore, the study also evaluated the effects of NHC  in human airway epithelium (HAE) cells grown in culture.  NHC was highly effective against SARS-COV-2 in HAE cell cultures, as well as against SARS-COV-1 and MERS in mice.  The effects of NHC were most pronounced when given prophylactically 2 hours before exposure to the virus, but it was also effective when given shortly after exposure to virus.

The authors point out that mice show a very rapid reaction to infection as compared to humans, and the expected result of treatment with NHC after humans develop symptoms would be seen at 5-7 days after infection, as compared to 12 hours after infection with mice.  Therefore, as with oseltamivir treatment of influenza, which is only effective when given within 5 days after symptom development, NHC would be given as early as possible after infection with SARS-COV-2.

There is no known mouse model of the effects of human aging on the clinical picture of infection with SARS-COV-2.  This limitation makes it harder to study the effectiveness of treatment with antivirals in humans, other than the tests done on cells in culture.  In the meantime, we will have to do with the modeling studies done in rhesus macaque monkeys, which show a similar clinical picture as in human COVID-19.  Fortunately, monkeys usually survive SARS-COV-2 infection even without treatment; they have been found to respond experimental vaccination well.

The authors state that NHC could be expected to have some effect in humans with severe COVID-19 later during the course of illness because virus shedding continues longer.  The evidence in autopsies shows widespread thrombosis and angiogenesis (new, tiny blood vessel formation) in the lungs.  The clinical picture in severe COVID-19 also appears to be dominated later in the course by “cytokine storm” so there is precedent for additional treatment to reduce the inflammatory response and thrombogenesis (production of blood clots) in late, severe disease.

In summary, the authors advise further development of NHC with human trials in COVID-19, in which the drug should be given as early as possible after infection.  In addition, “NHC is broadly active against multiple genetically distinct viruses including VEEV, influenzas A and B, Ebola, and Chikungunya viruses.”  Therefore, the drug should be evaluated against other epidemic viruses which may strike the human population in the future.

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