Corona is still on the brink of trouble in two projects. One approach is researching the targeted gene regulation of the virus, the other is to block a virus protein that is important for virus replication.
Researchers at Goethe University in cooperation with other institutions want to use small active ingredient molecules SARS-CoV-2 paralyze. Small molecules are often used in drug discovery because they can penetrate human cells more easily than large molecules and because they are relatively easy to synthesize. If a potential target structure – such as a virus – is known, entire libraries of such small molecules can be searched in order to identify the candidates that bind to the target structure.
Searching for active ingredients: start with the RNA
The project Target-RNA-antiV When searching for active substances, it starts directly with the viral genome RNA. Prof. Maike Windbergs and Prof. Harald Schwalbe and Dr. Julia Weigand up Work of the international COVID-19 NMR consortium which has identified a total of 15 control elements in the genome of SARS-CoV-2. With their help, the virus directs the infection process in the human cell.
One of these control elements is the focus of Target-RNA-antiV. It is a kind of switch with which the virus can produce two different virus proteins from the same piece of genetic material (RNA pseudo-node element). The scientists will look for small molecules that block this switch so that the virus can no longer make a number of important proteins. Promising drug candidates will then be sprayed onto 3D cell culture models of the human lungs in order to test their potential applicability as a therapeutic agent.
Macro domain as a point of attack
The project CoVmacro focuses on the viral protein nsP3, with the help of which SARS-CoV-2 prevents, among other things, the cellular defense reaction. We already had that a certain part of nsP3, the so-called macro domain, can be a target for drugs previous work be able to show. With the help of the macro domain, the virus ensures that cells are no longer able to activate signaling pathways for stress and defense reactions. Biochemically, the viral macrodomain prevents the sugar ADP-ribose from being attached to corresponding cellular signal proteins in order to activate the signal chain.
Together with his team, Prof. Stefan Knapp is looking for small molecules that can inhibit the viral macrodomain and thus strengthen the cell’s own defenses. Since the macro domain in many other coronaviruses, in Hepatitis E viruses and Alphaviren like that Chikungunya-Virus has a very similar structure, possible therapeutic approaches could apply to other viral diseases.
This article is based on one Press release of the Goethe University Frankfurt am Main. We have linked the mentioned works to you in the text.
Image source: Fusion Medical Animation, unsplash