9 Jun 2020

Molecular block of the SARS-CoV-2 virus being explored

Tight binding of α-ketoamide molecules (red), in the active
 site (gold) of the SARS-CoV-2 main protease.
Dr Tom Karagiannis and colleagues are examining the binding of small molecules to a particular protein of the SARS-CoV-2 virus, to block its action.

Dr Karagiannis said, "The main protease is a non-structural protein that the SARS-CoV-2 virus needs to replicate.  Once inside the host cell, the virus makes proteins so it can produce more copies of itself. These proteins need to be processed and proteases such as the main protease are responsible for cleaving the proteins at specific sites.

"By blocking the main protease you could stop the virus from replicating, which is what we're testing with a designer molecule called α-ketoamide." 

If α-ketoamide binds more tightly to the active site, does that stop the virus from binding to body sites (such as ACE2 receptors)?
It can stop the virus from replicating which can then stop the release of new virus particles and infection of other cells in the body.

If what you've done is more stable i.e. binds them for longer, will it be a better prophylactic?
The binding needs to be tight and long-lived so you can effectively stop the function of the protease.  We found that α-ketoamide binds in the active site and is stable over a long simulation period.

When you say 'potential antivirals', will or could the molecule be used for broad-spectrum antivirals, i.e. for different kinds of viruses?
That's right. α-ketoamide was initially developed for SARS, and has been shown to work in many kinds of viruses, including enteroviruses and coronaviruses, because the active site of these proteases is highly conserved. 

Where do α-ketoamides come from? You said this was a designed compound, an analogue. Do we already use them in other medicines?
These are designer molecules that mimic peptides and were specifically designed to inhibit viral proteases.  Currently, improvements are being made so that these molecules can be administered by inhalation to target the respiratory tract.

Dr Karagiannis is head of the Epigenomic Medicine research group in the Central Clinical School's Department of Diabetes.

Liang J1, Pitsillou E1, Karagiannis C2, Darmawan KK3, Ng K4, Hung A3, Karagiannis TC5. Interaction of the prototypical α-ketoamide inhibitor with the SARS-CoV-2 main protease active site in silico: Molecular dynamic simulations highlight the stability of the ligand-protein complex. Comput Biol Chem. 2020 May 28;87:107292. doi: 10.1016/j.compbiolchem.2020.107292.

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