Antiviral Drug Discovery against Hemorrhagic Fever Viruses

Emerging viruses such as Lassa Virus (LASV), Ebola Virus (EBOV) or Crimean Congo Hemorrhagic Fever Virus (CCHFV) are a major threat in their endemic countries and have the potential to cause epidemics. The development of specific couter measures has been hampered by a lack of commercial interest as the diseases caused be these viruses are rare and research and development is complicated by the need to handle these viruses in biosafetly level 4 laborytories.

One common approach to identify antiviral drugs for the treatment of such so called orphaned diseses, is drug repurposing. In this approach, libraries of drugs that have been developed for other applications are tested and efficacious compounds might then potentially be used off-label for the treatment of a different infection. The first step in this process is usuall to test a large number of drugs for aniviral efficacy and cytotoxicity on cells. Promissing compounds can be evaluated is dose response experiments on different cell lines. Finally, compounds with good antiviral efficacy and a favourable toxicity profile will evaluated in small animal models.

Recombinant reporter viruses that express for example a fluorescence proteine or a luciferase are good tools to facilitate these initial screening experiments as they simplify the readout for virus replication and allow for fast and large scale evaluation of drus collections. We developed a luciferase expressing LASV that can be used to screen for potential new antiviral drugs against this important emerging virus. Both commercial and academic drugs libraries are currently being screened with this virus. The development for similar screening assays for EBOV and CCHFV are ongoing.

   

[Translate to English:] Der Ablauf von Screenings von Virostatika ist dargestellt. Die genetischen Komponenten eines rekombinanten LASV sind eingezeichnet. Zellen werden mit den Viren infiziert und mit Virostatika behandelt. Mittels verschiedener Analysemethoden wird getestet, ob das Medikament einen Effekt zeigt.
Antiviral Screening with reporter viruses. A recombinant LASV expressing Metrida luciferase has been generated by duplicating the S segment of the virus genome and replacing on one segment each the open reding frame for GP and NP with the lucifease gene (1). After the infection of cells (2), metridia luciferase gets produce as a "viral gene" (3) and the quantification of the luciferase activity can be used as a measure of virus replication (4). The treatment of the infected cell with different antiviral compounds (5) and the measurement of the luciferase acitivity is an easy and fast way to identify drugs that interfer with virus replication. These drugs can in further experiments such as dose-response and cytotoxicity experiments be evaluated for their antiviral efficacy (6).   ©Lisa Oestereich (created with Biorender.com)

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