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Development of the natural compound silvestrol as antiviral drug candidate for hepatitis E virus and emerging RNA viruses. Short title: SILVIR

INNT

Project duration: 03/2019 - 02/2023

Funding: Federal Ministry of Education and Research

 

Research objective:

Recent outbreaks of viral infections, like Ebola virus and Zika virus, have highlighted the importance of their prevention in order to ensure public health in times of globalization. However, many viral diseases lack prophylactic vaccines and efficient therapies. Thus, identifying novel antivirals is of critical importance. SILVIR aims to develop silvestrol as a drug candidate for hepatitis E virus and emerging RNA viruses, which can cause global pandemics. Silvestrol is a metabolite from Aglaia plant with proven antiviral activities against several RNA viruses.

Methodology:

A medicinal chemistry program and hit to lead optimization of the natural compound combined with in-depth in vitro and in vivo characterization of lead candidates will guide a new antiviral treatment approach. Following this procedure, a virological in depth characterization, including mode of action studies like ribosomal and resistance profiling with HEV as model virus, will be performed. Silvestrol modifications will be investigated in in vitro virus replication and infection assays. Semi-synthesis and in vitro studies will interact as an internal loop composed of iterative optimization steps. From these optimizations one or two lead structures will be identified. These lead derivatives will be generated in larger amounts for the use in preclinical animal model systems. Furthermore, as examples for other emerging viruses, RVFV, CCHFV and Hazara will be tested for their susceptibility to silvestrol. After the successful development and characterization of a lead candidate a translation to human application is planned in collaboration with our clinical partners and established clinical trial units. To our knowledge, to date no development of silvestrol (derivates) or any other compound as anti-HEV medication is ongoing.

As a result of the emergence of SARS-CoV-2, the studies on the antiviral effect of silvestrol and other active substances were also extended to this pathogen in spring 2020 (BMBF suggestion).

Involved INNT scientists:

Dr. Markus Keller
Dr. Martin Eiden
Prof. Dr. Martin H. Groschup

Dr. Saskia Weber (PostDoc)

Logo SILVIR

Project partner:

Prof. Dr. Eike Steinmann
Ruhr-Universität Bochum, Deutschland
https://www.ruhr-uni-bochum.de/virologie/

Prof. Dr. Andreas Kirschning
Leibnitz-Universität Hannover, Institut für Organische Chemie, Hannover, Deutschland
https://www.oci.uni-hannover.de/de/kirschning/