HIPS-Talk: “Hit-Identification Strategies for Anti-Infective Development“
The challenges associated with anti-infective drug-discovery programmes can be tackled by adopting several hit-identification strategies in parallel. This approach will be illustrated using one target enzyme from the methyl erythritol phosphate pathway. This pathway provides a rich source of drug targets given that pathogens such as Mycobacterium tuberculosis and Plasmodium falciparum use this pathway for the biosynthesis of the essential isoprenoid precursors isopentenyl dipohsphate (IPP) and dimethylallyl diphosphate (DMAPP), while humans exclusively utilise the alternative mevalonate pathway. Our target enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXS) catalyses the first and rate-limiting step of the non-mevalonate pathway. To facilitate the development of potent and selective inhibitors of DXS, we have explored ligand- and structure-based virtual screening, phage display, dynamic combinatorial chemistry and de novo fragment-based design. The most promising hits display inhibitory potency in the low micromolar range and promising activities in cell-based assays against P. falciparum and even drug-resistant strains of M. tuberculosis. Further assays demonstrated their selectivity over mammalian TDP-dependent enzymes.
 T. Masini, A. K. H. Hirsch, J. Med. Chem. 2014, 57, 9740–9763.
 J.-L. Reymond, M. Awale, ACS Chem. Neurosci. 2012, 3, 649–657.
 M. Mondal, A. K. H. Hirsch, Chem. Soc. Rev. 2015, 44, 24552488
T. Masini, J. Pilger, B. S. Kroezen, B. Illarionov, P. Lottmann, M. Fischer, C. Griesinger, A. K. H. Hirsch, Chem. Sci. 2014, 5, 3543–3551.
 A. K. H. Hirsch, J.-L. Reymond, T. Masin, C. Simonin. EP15160746.2.
Gebäude und Raum
Blg E8.1, Seminarraum (Erdgeschoss)
Anna Hirsch, Ph.D., is Associate Professor of Structure-Based Drug Design at the Stratingh Institute for Chemistry at the University of Groningen. She read Natural Sciences with a focus on Chemistry at the University of Cambridge and spent her third year at the Massachusetts Institute of Technology doing a research project with Prof. Timothy Jamison on the total synthesis of amphidinolide T1.
For her Master’s project, she returned to Cambridge to develop the double conjugate addition of dithiols to propargylic carbonyl systems reaction in the group of Prof. Steven V. Ley.
She received her Ph.D. from the ETH Zurich in 2008. Her research was carried out in the group of Prof. François Diederich and was aimed at the rational design and the synthesis of the first inhibitors for an enzyme as a novel approach to treat malaria.
Subsequently, she joined the group of Prof. Jean-Marie Lehn at the Institut de Science et d’Ingénierie Supramoléculaires (ISIS) in Strasbourg, before taking up her current position in 2010. Her work focuses on rational approaches to drug design (with a strong focus on anti-infective targets), including structure- and fragment-based drug design in combination with dynamic combinatorial chemistry.
Prof. Dr. Rolf Hartmann