When a cell is infected, SARS-CoV-2 does not only cause the host cell to produce new viral particles. The virus also suppresses the defense mechanisms of host cells. The viral protein nsP3 plays a central role in this regard. Using structural analyzes, researchers at Goethe University, in cooperation with the Swiss Paul Scherrer Institute, have now found that a breakdown product of the virostatic agent remdesivir binds to nsP3. This points to another, previously unknown, effective mechanism of remdesivir that may be important in the development of new drugs to combat SARS-CoV-2 and other RNA viruses.
The virostatic agent remdesivir was developed to disrupt an important step in the spread of RNA viruses, to which SARS-CoV-2 also belongs: the reproduction of the virus’s own genetic material. This is present in the form of RNA templates with which the host cell directly produces viral proteins. However, to speed up the production of its own proteins, RNA viruses copy RNA templates. To do this, they use a specific protein of their own (an RNA polymerase), which is blocked by remdesivir. Strictly speaking, remdesivir does not do this on its own, but rather a substance that is synthesized from remdesivir in five steps when remdesivir enters a cell.
In the second of these five steps, an intermediate is formed from remdesivir, a substance with the somewhat unwieldy name GS-441524 (in scientific terms: a metabolite of remdesivir). GS-441524 is also a virostatic agent. As scientists in the group led by Professor Stefan Knapp from the Institute for Pharmaceutical Chemistry at Goethe University in Frankfurt have discovered, GS-441524 targets a SARS-CoV-2 protein called nsP3. nsP3 is a multifunctional protein, the tasks of which include suppressing the defense response of the host cell. The host cell is not powerless against a viral attack, but activates inflammatory mechanisms, among others, to mobilize the help of the endogenous immune system of the cell. nsP3 helps viruses suppress cell calls for help.
Professor Stefan Knapp explains: “GS-441525 inhibits the activities of an nsP3 domain which is important for virus reproduction, and which communicates with human cellular defense systems. Our structural analysis shows how this inhibition works, allowing us to lay an important foundation for the development of new and more potent antiviral drugs – effective not only against SARS-CoV-2. The target structure of GS-441524 is very similar in other coronaviruses, for example SARS-CoV and MERS-CoV, as well as in a series of alphaviruses, such as chikungunya virus. For this reason, the development of these drugs could also help prepare for future viral pandemics.
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