Project C05.2

Arena- and phenuiviruses are emerging pathogens causing severe diseases, including viral hemorrhagic fevers, for which no approved antiviral therapies exist [1]. Several members, such as Lassa virus (LASV) and Severe Fever with Thrombocytopenia Syndrome Virus (SFTSV), are classified by the World Health Organization as priority pathogens [2]. The viral L protein, a multifunctional enzyme containing the RNA-dependent RNA polymerase, is essential for viral replication and transcription and therefore represents an attractive antiviral target [3-5]. 

This PhD project aims to identify and characterize small-molecule inhibitors targeting the L protein of LASV and SFTSV. High-throughput-suitable fluorescence polarization and homogeneous time-resolved fluorescence assays will be used to screen a large small-molecule library. Hit compounds will be validated and optimized through structural, biochemical, and computational analyses, including structure–activity relationship studies. Antiviral activity and cytotoxicity will be assessed in cell-based infection models, and selected compounds will be evaluated for broad-spectrum activity against related bunyaviruses. Structural analysis of L protein–inhibitor complexes by cryo-electron microscopy single-particle analysis, together with functional assays, will further define mechanisms of action. Embedded in an interdisciplinary research environment at the BNITM, CSSB, and the Fraunhofer ScreeningPort, this project aims to yield novel small-molecule inhibitors with antiviral activity and provide structural insights into their mechanisms of action.