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ESR-5 Molecular mechanism of highly potent NS5A inhibitors of hepatitis C virus

Project description
Hepatitis C virus (HCV) is a major causative agent of acute and chronic liver diseases, including liver cirrhosis and hepatocellular carcinoma. With the advent of robust cell culture systems, highly potent antiviral drugs have been developed and recently approved for treatment of chronic hepatitis C. One class of these inhibitors targeting nonstructural protein 5A is extremely potent and acts via a bimodal activity: blocking the assembly of virus particles and the biogenesis of the membranous replication factory (Berger et al., Gastroenterology 2014; Paul and Bartenschlager Cell Host & Microbe 2014; Bartenschlager et al., Nature Rev. Microbiol. 2013). However, the molecular mechanisms underlying this bimodal activity are not understood and will be addressed in this project. The ESR will use a combination of molecular, biochemical and advanced imaging-based methods, including live-cell imaging and correlative microscopy to decipher how NS5A inhibitors interfere with the formation of infectious virions and at the same block the membrane rearrangements that are essential to build up the viral replication factory. In addition, in a collaborative effort molecular docking will be used, complemented by reverse and forward genetics conducted by the ESR to decipher how NS5A interacts with the membrane, with viral RNA and with itself and how this might be affected by highly potent NS5A inhibitors.

The Network
This PhD position is part of the European training network ANTIVIRALS (www.antivirals-etn.eu). The candidate will benefit from the ANTIVIRALS network, which includes regular (scientific) network meetings and training in research methodology and complementary skills. This research project offers unique opportunities for establishing a broad and international scientific network with partners from the academic and industrial sector. The research project is performed in close collaboration with and partly at the premises of other institutions of the ANTIVIRALS network.

Host institute
Heidelberg University (HDU) is a public research university founded in 1386 and thus the oldest university in Germany. HDU has a strong emphasis on research, has been associated with 56 Nobel Prize laureates and is consistently ranked among Europe's top overall universities. HDU is an international education venue for doctoral students, with approximately 1,000 doctorates successfully completed every year, and with more than one third of the doctoral students coming from abroad. The Department of Infectious Diseases has access to numerous core facilities, including the Nikon Imaging Center, the DZIF BSL-3 live cell imaging facility and the electron microscopy core facility of the cluster of excellence “CellNetworks”. Furthermore, the Department is integrated into large national and international collaborative research projects offering strong expertise in molecular and cell biology research, biochemistry as well as applied research with a focus on drug development.
The research at the Department of Infectious Diseases, Molecular Virology, focuses on human pathogenic and medically relevant viruses that are responsible for chronic liver diseases (hepatitis B virus, hepatitis C virus) and for mosquito-transmitted infections (Dengue virus, West Nile virus). Projects conducted in the Molecular Virology research unit aim at understanding the cell biology underlying the replication cycle of these viruses, how these infections causes disease and which mechanisms these viruses use to overcome the innate immune responses. One important aspect is to translate our findings into the clinic, for which we have established translational collaborative research projects.
Research of the ESR will be embedded in the Graduate School of the Department of Infectious Diseases in Heidelberg. This Graduate School offers a structured program and multiple opportunities for collaborative studies related to human-relevant pathogens, immunology, biochemistry, structure and cell biology as well as systems biology. In addition, a strong link has been implemented to the German Cancer Research Center, where tumor-relevant viruses are studied.

Candidate found. Vacancy is closed.