Structure-activity relationship studies of Zn(II)-BnPyP for the development of dual anti-prion drugs

Genetic prion diseases are rare, deadly, and progress quickly. They happen because the normal prion protein (PrP^C) changes into a harmful form (PrP^Sc). Currently, there are no approved treatments for these diseases. We discovered that a molecule called Zn(II)-BnPyP can effectively combat prion diseases through a dual mechanism: by interacting with PrP^C, it blocks PrP^Sc formation and reduces PrP^C levels. Even if Zn(II)-BnPyP cannot easily enter the brain, limiting its effectiveness as a treatment, it gives us a valuable chance to understand the characteristics a molecule must have to achieve a dual anti-prion effect.

Using advanced techniques like NMR spectroscopy and computational calculations, we aim to create structural models showing how Zn(II)-BnPyP interacts with PrP^C. Then, as both metal and chemical groups of Zn(II)-BnPyP affect its anti-prion activity, we will study different versions of this molecule. We will make Zn(II)-BnPyP derivatives with various metals or chemical groups and examine how well they bind to PrP^C and affect its structure. We will also test the ability of these derivatives to reduce PrP^C levels in cells, inhibit PrP^Sc replication, and their overall effectiveness against prion diseases in cellular models.

Thanks to this project we will identify the best metal and chemical groups for optimal interaction with PrP^C and strong dual anti-prion activity. Thus, we could develop new compounds with drug-like properties and a more potent mechanism of action with respect to the anti-prion molecules studied so far, as they will block PrP^Sc formation and reduce PrP^C at the same time.