Progetti di ricerca

One of the most promising directions in contemporary drug discovery research is based on targeting non-native proteins conformations (e.g. so–called cryptic pockets). In particular, authors involved in this proposal have been involved in conceiving and developing a novel paradigm called PPI-FIT (defined below),… Leggi tutto which is based on hindering the folding of the target protein. This approach led to the discovery of SM875, a small molecule capable of selectively reducing the cellular levels of the human prion protein (PrP), the substrate of prions, infectious protein aggregates involved in several fatal incurable neurodegenerative diseases. A crucial piece of information required in the hit-to-lead optimization of cryptic pocket drug candidates (including SM875) is the atomic resolution of the structure of the binding pose. In conventional drug discovery efforts, this information could is obtained by X-ray crystallography or NMR experiments. Unfortunately, these techniques cannot provide the structure of unstable protein conformers, even when they are stabilized by the interaction with a small molecule, like SM875 does for PrP, because of their high aggregation propensity. Several recent studies have highlighted the unique advantage of performing protein crystallization in microgravity conditions1. The primary goal of this proposal is to define a roadmap to further develop such a space-based technology to achieve the crystallization of protein non-native conformers, by assaying different experimental protocols. Our experimental setup will be first tested in a pioneering experiment, included in the upcoming SpX27 space mission. The goal of the present proposal is to capitalize on the preliminary results generated by this first mission to further develop this technology, leading to a stable, scalable, and versatile protocol for crystallizing non-native protein conformers in microgravity conditions.