My current scientific activity focuses on the modulation of metalloproteases using small chemical compounds.

•  Since 2007, my team developed a targeted library of zinc-binding compounds that allowed exploring the several metalloprotease families. Therapeutic applications of inhibitors of such enzymes include infectious, immune and metabolic diseases.  In the M1 family, we discovered the first drug-like inhibitors of the plasmodial aminopeptidase PfAM1 a malarial protease (J. Med. Chem 2007 & 2012) and original neutral aminopeptidase APN inhibitors (Bioorg. Med Chem 2007).  In the M12 family, we focussed on aggrecanases inhibitors (Fut. Med. Chem. 2014, Eur J Med Chem 2013, Bioorg Med Chem Lett 2010). For neprilysin (M13 family) we designed new inhibitors (MedChemComm 2012) using solid phase synthesis on lanterns.
• In the past years, we have been studying Insulin Degrading Enzyme (IDE, M16 family) to decipher its complex role in Type-2 diabetes and Alzheimer’s disease thanks to pharmacological chemical probes. We disclosed the first exosite binders (Eur JMedChem 2014 & 2015), the first cell-penetrant, in vivo active IDE inhibitor using an original KTGS based on hydroxamic acids, and demonstrated that acute IDE inhibition induced a paradoxical glucose intolerance, in line with the phenotype of the IDE-KO animals (Nature Comm 2015, Elife 2018). We also showed that Ebselen is the most potent inhibitor of IDE (Eur JMedChem 2019). We are also interested in the Aminopeptidases of the ER (ERAP, M1 family) inhibitors (ACS Med Chem Lett 2017).
• For our projects targeting metalloproteases we developed an expertise in hydroxamic acids (and other zing binding groups), in Kinetic Target guided synthesis (Nature Comm 2015, Fut. Med. Chem. 2016, J Med Chem 2020) and in tools to measure biological stability of chemical compounds (JMedChem 2017, Lancet 2018) and target engagement using CETSA (SLASDiscov 2020). In particular for hydroxamic acids, we designed the first medchem toolbox to optimize their plasma stability (JMedChem 2009 & 2017)
• Also we developed several chemical methodologies to access bioactive compounds, heterocycles and original nature-inspired compounds. We disclosed the original synthesis of oxadiazoles (Tet lett 2001, Nature Med 2009), solvent-free microwave irradiation to access bicyclic lactams (Green Chem 2010,2012), polymer-supported chemistries (BMCL 2009, Eur J Med Chem 2011, MedChemComm 2012), use of T3P (Tet Lett 2012), or water-based synthesis (TetLett 2013).