Prof. Gerd Klebe (PUM), Dr. Wolfgang Jahnke (NOVA)
Fragment-based approaches to block protein functions at the example of FarnesylPyrophosphate Synthase (FPPS) and other model proteases.
About the project:
FPPS is a key enzyme in the metabolic mevalonate pathway. This target protein is important to treat protozoan parasite diseases such as Chagas disease and Sleeping Sickness, which are caused by T.cruzi and T.brucei, respectively. Typical inhibitors for FPPS are bisphosphonates. Unfortunately, due to their poor pharmacokinetic properties, the known bisphosphonates should be replaced with new selective compounds having a different mechanism of action. A promising candidate is the regulation of the allosteric pocket.
Using a crystallography-oriented fragment-based lead discovery approach, new ligands can be generated by targeting allosteric binding pockets of FPPS. The optimization and validation of the initial hits will be performed using MCR. By exploring the chemical space around the hits, it will be possible to determinate the structure-activity relationship. The activity and kinetic properties of the compounds will be evaluate using SPR and ITC.
Francesca graduated with a Master’s Degree in Pharmaceutical Chemistry and Technologies at the University of Cagliari in 2015. During her master’s thesis, she worked under the supervision of Prof. Dr. E.Maccioni in collaboration with Prof. Dr. Kikeli from the University of Ljubljana. Her project aimed at the synthesis of new compounds with antibacterial activity. During this period, she acquired knowledge in synthesis, purification, structural characterization, and the design of new compounds. From October 2015 to March 2016, she did an internship with Prof. Dr. Klebe from the Philipps University of Marburg. There she gained new research experience by learning the techniques of protein expression and purification, crystallization, and soaking. Since April 2016, she started her PhD project in the same research group.
NIBR (Novartis Institute for Biomedical Research) Basel, Switzerland (2 months)
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Institut für Pharmazeutische Chemie
Marbacher Weg 6