Prof. Dr. Anna K.H. Hirsch “Hit-Identification Strategies for Anti-Infective Development“

HIPS Talk
Prof. Dr. Anna K.H. Hirsch
Department of Chemical Biology,
University of Groningen
will give a presentation entitled
“Hit-Identification Strategies for Anti-Infective
Development“
Friday, March 4, 2016, at 11:00 s.t.
in Blg E8.1, Seminar Room (Ground Floor)
Host: Prof. Dr. Rolf Hartmann
There is opportunity to talk with the speaker before the talk.
There will be a follow-up session (Nachsitzung).
For details and for making appointments please contact: May Küffner,
0681-98806-2001 or per email: [email protected]
Guests are welcome!
HIPS Talk
Abstract
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.[1] Our target enzyme 1-deoxyd-xylulose-5-phosphate synthase (DXS) catalyses the first and rate-limiting step of the nonmevalonate pathway. To facilitate the development of potent and selective inhibitors of DXS,
we have explored ligand-[2] and structure-based virtual screening, phage display, dynamic
combinatorial chemistry[3] and de novo fragment-based design.[4] 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.[5]
Bibliographic references:
[1] T. Masini, A. K. H. Hirsch, J. Med. Chem. 2014, 57, 9740–9763.
[2] J.-L. Reymond, M. Awale, ACS Chem. Neurosci. 2012, 3, 649–657.
[3] M. Mondal, A. K. H. Hirsch, Chem. Soc. Rev. 2015, 44, 24552488
[4]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.
[5] A. K. H. Hirsch, J.-L. Reymond, T. Masin, C. Simonin. EP15160746.2.
CV
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 antiinfective targets), including structure- and fragment-based drug design in combination with
dynamic combinatorial chemistry..