B1: Dengue and Zika virus, design of inhibitors of NS3/NS2B serine protease.

Project description:

Infections with the dengue virus have reached a new high in recent years, with around 50-100 million new infections per year. In the vast majority of cases, the infection progresses with mild, flu-like symptoms, but a small percentage of those affected, often children, develop hemorrhagic fever, which is fatal if severe. Although a vaccine is now available, since this is only approved for a very limited group of people, the development of agents that efficiently suppress the multiplication of the virus is essential. Our work focuses on the virus’s own serine protease NS3/NS2B, which cleaves the viral precursor protein into functional proteins and is essential for the maturation of the virus.

Abb. B1. Kristallstruktur der NS3/NS2B Protease DENV 3.1

Scientific goal:

The aim of the project is to further develop allosteric inhibitors of the viral serine protease NS3/NS2B, not only with respect to their affinity, but also with respect to their pharmacokinetic properties and toxicity (hit-to-lead development) using a combined approach of computer-aided design, synthesis, biological assays and crystal structure analysis. In addition, inhibitors of the related Zika protease will be developed based on the knowledge gained.

DRUID Collaboration partners:

A1 Becker, A2 Grünweller, B3 Rahlfs/Kolb/van Zandbergen, XY Herker, E6 Schiffmann/Laux

References B1: [1] Noble et al. (2012) J Virol 86(1):438-446; *[2] Chevillard et al. (2015), J Chem Inf Model 55(9):1824-1835; *[3] Chevillard et al. (2018) J Med Chem 61(3):1118-1129