Target metalloproteases thanks to a chemo-genomic strategy.
Modern chemistry techniques allow for the generation of a vast number of compounds and an even greater amount of data. Chemoinformatics refers to the building of electronic databases of the chemical and biological properties of large numbers of chemical compounds. One application of the mining of very large datasets of chemical and biological information is chemical genomics or "chemogenomics", which uses drug-like compounds as molecular probes for cell-biology research, to clarify for example the function of a certain gene product. Because it integrates chemistry and biology already in an early stage in the research process, "chemogenomics" is a technologic bridge between genetic and therapeutic research areas. Continuation of a pilot chemogenomics project supported by the Nord-Pas-de Calais Region and FEDER, this project federates several labs around the study of metalloproteases, according to a strategy which takes root into the regional scientific environment, with special focus on the exploitation of the Regional Screening plateform maintained in our lab and of a DNA microarray designed to represent all expressed human metalloproteases
Metalloproteases are a class of proteins involved in diverse and important biological phenomena such as cell proliferation, signalisation, multiplication and migration, hormonal signalisation, angiogenesis, pathogen growth. Numerous inhibitors of this enzyme class are described and some are important therapeutic classes: ACE or NEP inhibitors. This context justifies for the systematic search of metalloproteases implication in orphan pathologies, as well as for their expression, purification and crystallisation, or for the design and synthesis of a targeted library of inhibitors.
Having a strong background in the inhibition of parasitic metalloproteases (PfA-M1) (http://dx.doi.org/10.1021/jm061169b) and their human orthologues (APN) (http://dx.doi.org/10.1016/j.bmc.2006.10.010), our group has designed and synthesized 1500 Zinc ligands that will be tested on a panel of 10 metalloproteases. The goals of the project are 1/ finding inhibitors of the chosen targets, 2/ validating these targets in vitro and in vivo in cellular or animal models, 3/ developing new drug lead series. Already 5 screening campains on metalloproteases have been performed see the poster proposed at the SBS (Society for Biomecular Screening) 15th Annual Meeting Apr. 26-30 2009. Using this strategy, novel drug-like inhibitors of Neutral Endopeptidase and Aggrecanase-2 have been found and optimized. Also the first modulators of insulin degrading enzyme have been found.
Deprez-Poulain, R., Flipo, M., Piveteau, C., Leroux, F., Dassonneville, S., Florent, I., Maes, L., Cos, P., & Deprez, B. Structure-Activity Relationships and Blood Distribution of Antiplasmodial Aminopeptidase-1 Inhibitors. Journal of Medicinal Chemistry,2012, 55(24): 10909. doi: 10.1021/jm301506h
When targeting metalloproteases, a ZBG is necessary to bind to the Zinc ion and sets the rest of the molecule in the active site. Using hydroxamate is convenient to achieve good activity at the screening stage because this function is one of the best Zn ligand. Nevertheless, a high binding to the target can be achieved with a "softer" ZBG, provided that the rest of the molecule fits nicely in the binding pocket. Furthermore, because hydroxamic acids are often poorly absorbed and are prone to metabolic degradation and glucuronidation, there has been considerable interest in discovering alternative groups that can be incorporated in the structures of metalloproteases inhibitors. The search of relevant new zing binding groups is widely investigated. ZBG can be classified in two classes 1) monodentate that include thiols, carboxylic acids, acidic heterocycles, phosphinic acids...2) bidentate that include hydroxamate and hydroxypyridones. Recent examples of the use of heterocyclic ZBGs include hydantoines, triazolones and imidazolones as inhibitors of TACE (TNF-alpha converting enzyme) or tetrazoles as inhibitors of metallo-beta-lactamase.
We have developped chemical strategies to synthesize in parallel, either using solution-phase or solid-phase synthesis, the following compounds: tetrazoles, squaric acid derivatives, 1,3,4-triazole-thiols -1,2,4-oxadiazol-ones or –thiones…