Structure-Based Design and Optimization of AIF/CypA peptide inhibitors with neuroprotective activity

In this research work, we described the importance of peptides as a therapeutic approach for the resolution of many diseases. In particular, we focused our attention on the lethal role of complex protein AIF/CypA, involved in neuronal cell death. The aim of this project was the structure-based design and optimization of AIF/CypA peptide inhibitors, using NMR studies and combinatorial chemistry. The peptides were designed from AIF(370-394) peptide, mimetic of amino acidic region 370-394 of AIF protein, able to block in vitro the proteins interaction, through its bond to CypA and able to induce neuroprotection. The identified peptides will be used to for the treatment of neurodegenerative disorders. Moreover a second project was focused on development of a simple and homogenous fluorescent HTS assays for the discovery of CypA cis-trans isomerase activity inhibitors, using a new FRET-based substrate probe useful for Chymotrypsin-coupled isomerase assays. For this purpose, we have designed a new fluorescent peptide substrate, useful to the use of in order to have a high proportion of cis conformers and to work by following fluorescence intensity increase or decrease, depending on enzyme activation or inhibition. The assay is helpful to screening set of large compound libraries.