Small molecules to treat protein misfolding diseases

The disorders caused by destabilizing mutations are named conformational diseases. They count several rare genetic diseases among which TTR- amyloidosis (ATTR) and PMM2- congenital disorder of glycosylation (CDG). There is still no cure available to these patients. ATTR and PMM2- CDG are exemplary of the routes that unstable proteins can undergo: protein accumulation as toxic fibrils or protein elimination causing loss of function. Both outcomes can be prevented by acting upstream on protein stabilization. Native transthyretin (TTR) is a homotetramer. Missense mutations lead to unfolding into monomers followed by the formation of oligomers and then amyloid fibril deposition. Iodinated 4,4'-bipyridines were characterized as TTR stabilizers. The compounds' activity in vitro was assessed monitoring the fibril formation by a turbidity assay. Three ligands, named (M)-8, (M)-9 and (P)-9, resulted effective in preventing the change of wild type and mutants TTR conformation [1]. Mutations in the enzyme phosphomannomutase2 (PMM2) affecting N-glycosylation of protein lead to the most frequent glycosylation defect. b glucose-1,6-bisphosphate (?G16) was identified as a pharmacological chaperon as it enhances PMM2 stability preventing its degradation. The binding of ?G16 to the protein causes a conformational change proved by in silico docking and by limited proteolysis. PMM2 stabilization in the presence of the ligand was measured using thermal shift assay [2]. Currently, we are refining a strategy to promote G16P bioavailability to be used for therapy. In our laboratory, we can analyze the ligand-protein interaction especially testing the effect of the compounds of interest on protein stability and activity. These approaches are useful in identifying potential drugs for protein misfolding disorders. [1] Dessì et al. 2020, Molecules. 25, 2213 [2] Monticelli et al. 2019, IntJMolSci. 20(17),4164.