ElteN378

α-Synuclein (α-syn), a disordered cytoplasmatic protein, plays a fundamental role in the pathogenesis of Parkinson's disease (PD). Here, we have shown, using photophysical measurements, that addition of FKBP12 to α-syn solutions, dramatically accelerates protein aggregation, leading to an explosion of dendritic structures revealed by fluorescence and phase-contrast microscopy. We have further demonstrated that this aberrant α-syn aggregation can be blocked using a recently discovered non-immunosuppressive synthetic inhibitor of FKBP12, ElteN378. The role of FKBP12 and of ElteN378 in the α-syn aggregation mechanism has been elucidated using molecular dynamics simulations based on an effective coarse-grained model. The reported data not only reveal a new potent synthetic drug as a candidate for early stage treatment of α-syn dependent neurodegenerations but also pave the way to a deeper understanding of the mechanism of action of FKBP12 on α-syn oligomeric aggregation, a topic which is still controversial.

Due to its central role in immunosuppression and cell proliferation and due to its specific peptidyl-prolyl-isomerase (PPI) function, the FKBP protein family is at the crossroad of several important metabolic pathways. Members of this family, and notably FK506 binding protein (FKBP12), are thought to be involved in neurodegenerative diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, amyotrophic lateral sclerosis, as well as in proliferation disorders and cancer. Using an interdisciplinary approach based on computational, synthetic, and experimental techniques, we show that the best potential binders for FKBP proteins optimally expose the two contiguous carbonyl oxygen in the proline-mimetic chain for FKBP docking and are characterized by the abundance of rigid quasi-cyclic structures stabilized in aqueous solution by intraligand hydrophobic interactions mimicking the macrolide structure of the natural FKBP binders FK506 and Rapamycin. These peculiar structural and chemical-physical features define at the same time an ElteX compound and the minimal pharmacore in the FKBP family, shedding new light on the isomerization mechanism of the PPI domain. On the basis of the above hypothesis, we have successfully designed and synthesized several nanomolar ElteX FKBP12 ligands. Among these, ElteN378 is a new low atomic weight ligand with affinity comparable to that of the macrolide Rapamycin.