ChemVsCOVID Medicinal Chemistry

#ChemVsCOVID: How nucleoside analogue antivirals combat COVID

Chem Vs COVID graphic: 22 October, FDA approves the first COVID-19 antiviral. Nucleoside analogues resemble the natural building blocks that make up virus RNA. The structural differences stop the virus RNA from being copied correctly. Remdesivir has since been shown to be ineffective, and the WHO has cautioned against its use, but another similar drug, molnupiravir, looks promising. Protease inhibitor drugs are also being investigated.
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One year ago, in October 2020, the US FDA approved remdesivir: the first antiviral drug approved for COVID-19. While it’s not as effective as was first thought, similar drugs look like they could be more successful. The latest graphic in the #ChemVsCOVID series with the Royal Society of Chemistry examines how they work.

Remdesivir is a nucleoside analogue. These are molecules which resemble the naturally-occurring building blocks that make up RNA, the molecule in which viruses encode their genetic material.

Viruses need to copy their RNA to make more copies of themselves, and the enzyme they use to do this is called RNA polymerase. RNA polymerase is a molecular copier that produces additional RNA strands. Nucleosides are the individual units in these strands. By mimicking their structures, nucleoside analogues get incorporated into the growing, copied RNA strand.

But, like a medical Trojan horse, once nucleoside analogues have tricked their way in, they cause chaos. They bring the RNA polymerase machinery grinding to a halt, stopping it from completing the copied RNA strand. This stops the virus from making copies of itself. It’s the subtle structural changes in nucleoside analogues that are responsible for this sabotage.

Take remdesivir: structurally, its active form looks very similar to adenosine, one of the nucleosides in RNA. One of these similarities is key: the two nitrogens in the top right of the molecule are identical to adenosine, so like adenosine they will form hydrogen bonds to uridine, another RNA nucleoside.

The significant difference between remdesivir and adenosine is the cyanide (-CN) group added in remdesivir. This affects the shape of the sugar part of the molecule, which in turn distorts the RNA strand. This makes it so that the RNA polymerase can only add three more nucleosides before it comes crunching to a halt.

Another nucleoside analogue, molnupiravir, has an even more cunning molecular disguise. Its active form actually has two forms, or tautomers, which can switch between one-another. One mimics one nucleoside, uridine, while the other form mimics another, cytidine. Again, subtle structural changes make molnupiravir differ from these nucleosides. Unlike remdesivir, these structural changes don’t directly stop the RNA copy being built. But because molnupiravir’s active form can appear as two different nucleosides it confuses the RNA polymerase when it tries to recopy the copied RNA, introducing copying errors that lead to the virus’s demise.

Despite being the first antiviral to be approved to fight COVID, remdesivir has already fallen out of favour. The World Health Organisation has stated that there is insufficient evidence that remdesivir is effective against SARS-CoV-2, the virus that causes COVID-19. Since November 2020, they have recommended against its use. A pill version is in development, which may be effective in given to patients in the earlier stages of the disease.

Molnupiravir, the other nucleoside analogue being pursued as a COVID-19 treatment, looks more positive. Clinical trials are ongoing, but current results show that it does appear to reduce the risk of hospitalisation and death from COVID-19. Several countries have preemptively put in orders, though it is yet to be approved. Though some safety concerns have been raised, and safety data has yet to be published, the drug passed phase 1 safety trials.

Nucleoside analogues aren’t the only COVID treatment drugs in development: protease inhibitor drugs have also shown promise. These drugs bind to the viral protease enzyme and stop the virus from copying itself. Pfizer’s PF-07321332 is an example which is currently in clinical trials.

Like vaccines, these antiviral medicines won’t eradicate COVID. But they will hopefully help us reduce the numbers of hospitalisations and deaths from the disease. With many governments now pursuing a plan of ‘learning to live with the virus’, this will be essential to reduce the numbers of preventable deaths.

This graphic was developed in partnership with the Royal Society of Chemistry. See the full #ChemVsCOVID series of graphics here.

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