HIPS-Talk: “Allosteric inhibitors of Dengue virus NS3/NS2B protease“
Dengue fever is a mosquito-borne tropical disease caused by the dengue virus. It is transmitted to humans by the Aedes aegypti and Aedes albopictus mosquitos. The Dengue virus genome encodes a serine protease with a classical catalytic triad (His51, Asp75 and Ser135) which is responsible for the post-translational proteolytic processing of the polyprotein precursor and which is essential for the viral replication, rendering it an important drug target.
Starting with a broad screening of our in-house compound library we identified diaryl (thio)ethers with benzothiazole fragment as candidates for a novel class of selective inhibitors of the serotype 2 and 3 Dengue protease. The compounds were optimized based on molecular docking studies which suggest binding at a specific allosteric binding site. In addition to fluorometric enzyme assays and ligand-binding studies via MST (microscale thermophoresis), a cell-based protease assay was developed to test these substances in a replication-independent way.
Gebäude und Raum
Blg E8.1, Seminarraum (Erdgeschoss)
Tanja Schirmeister received her PhD degree in Medicinal Chemistry from Freiburg University in 1993 (under the guidance of Prof. Dr. H.-H. Otto; topic: Enzymatic hydrolysis of E/Z-diastereotopic diesters and E/Z-diastereomeric halfesters). After the habilitation in 1999 (under the supervision of Prof. Dr. A. W. Frahm; topic: Cysteine protease inhibitors with aziridine building blocks) she received and accepted a call for a C3-professorship at the Institute of Pharmacy and Food Chemistry of the University of Würzburg in 2000. Since 2011 she holds the Chair of Pharmaceutical and Medicinal Chemistry at the Institute of Pharmacy and Biochemistry (IPB) of the Johannes-Gutenberg University of Mainz. She currently holds the directorship of the IPB
She was awarded with the Carl-Wilhelm-Scheele PhD Thesis Award of the German Pharmaceutical Society (DPhG), the Habilitation Award of the Medicinal Chemistry Sections of the German Chemical Society (GDCh) and the German Pharmaceutical Society (DPhG), and the Research Award „Eugen-Graetz-Stiftung" of the University of Freiburg.
Her research interests include the rational design of covalent enzyme inhibitors, the development of protease inhibitors, the development of new drugs against neglected diseases, and the bioactivity-guided identification of protease inhibitors from natural sources.plants, fungi and animals.
Prof. Dr. Rolf Hartmann