Inhibitors of flaviviral proteases with non-classical binding mode

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The principal aim of this project is to discover inhibitors of flaviviral proteases. Of particular interest are compounds that contain recognition elements capable of forming a covalent interaction with the catalytic serine. Equally important, an increased emphasis will be laid on the cellular activity of the protease inhibitors during the second funding period of this project. The recent outbreak of Zika virus infections has further increased the urgency to discover and develop therapeutical agents for the prevention and treatment of flaviviral infections. While Zika has received considerable public attention in the past months, it represents "only" an additional layer of disease burden on top of the already "established" flaviviral infections such as dengue and West Nile fever. From a public health perspective, development of vaccines clearly represents a very attractive strategy. However, decades of vaccine work on dengue virus, which only recently resulted in a vaccine with moderate efficacy, have shown that this is not a reliable option to deal with unexpected outbreaks of previously unknown or underattended pathogens such as Zika. We therefore consider it attractive to pursue the protease of flaviviruses, a virus-specific enzyme that is essential for replication of all flaviviruses, as a therapeutic target, with the aim to find agents with sufficient selectivity and, if possible, broad-spectral activity that potentially also includes as-yet unknown or less studied flaviviruses. While the serine protease of the closely related hepatitis C virus is a well-exploited drug target, similar efforts in the dengue and West Nile virus field have often remained fairly disappointing, and the pharmaceutical industry has therefore decreased the priority of respective drug discovery projects. Against these expectations, the first funding period of the current project resulted in the discovery of highly potent dengue and West Nile virus protease inhibitors which also show activity against viral replication in cell culture. The present continuation proposal intends to build on this success and to press ahead with the discovery and characterization of protease inhibitors with an improved in-vitro profile. A particular emphasis will be laid on compounds with a covalent binding mode that, at the same time, possess a suitable PK/ADME profile. At the same time, we intend to develop intracellular assay systems for viral protease activity, in order to bridge the gap between biochemical and phenotypic/antiviral assays.