JOB ALERT : 12 month post-doc position available, interface Chemistry/Biology

Design, synthesis and evaluation of fluorinated non-canonical peptides targeting Cathepsin D

Context and Project Objectives: Cathepsin D (CD) is one of the most abundant lysosomal protein responsible for the disposal of exhausted biomolecules.1 Significantly, CD deregulation can contribute to several human diseases, such as acute kidney injury, Huntington’s, Parkinson’s disease, Alzheimer’s disease (AD), and pancreatitis.2 Moreover, CD imbalance plays an important role in malignant tumors. Increased extracellular levels of CD were observed in breast, ovarian, colorectal, prostate, and bladder cancer.3 Therefore CD can be considered as an important target and potent inhibitors of Cathepsin D would help to precise its role in diseases and could lead to new therapeutics.4 Very recently, we found out that trifluoromethyl non-canonical peptides derived from Pepstatin A are selective and very potent CD inhibitors.5 As part of the ANR project FLUORAAC “Fluorinated cyclopropane amino acids: from synthesis to incorporation into peptidic structures for biological applications” bringing together the teams of Pr. Philippe Jubault and Dr Vincent Tognetti (CARMEN institute, UMR 6064, Rouen), DR. Florine Cavelier (IBMM, UMR 5247, Montpellier) and Prof. Julien Pytkowicz (BioCIS Laboratory, UMR 8076, Cergy-Pontoise), this task plans to incorporate fluorinated cyclopropane amino acids in the N-terminal part of Pepstatin A scaffold and test the resulting analogues as CD inhibitors. The mains objectives are:
- Synthesis (SPPS) and characterization of fluorinated Pepstatin A analogues
- Conformational studies and molecular docking experiments on a series of aspartic proteases
- Fluorescence and NMR-based biological evaluation of inhibitors activity