• fibril formation inhibitors
• Tranthyretin
• TTR-inhibitor crystal complex
• X-ray crystallography

Transthyretin (TTR) is a 54-kDa homotetrameric carrier of thyroxine and retinol binding protein (RBP) in human plasma and cerebrospinal fluid. TTR is stable and not dangerous in physiological condition. Unfortunately, under unknown conditions, TTR aggregates to form fibrils. The fibrils can cause dangerous deposits in human tissues associated with a variety of diseases classified as “Transthyretin-mediated amyloidosis” (ATTR). One therapeutic approach for ATTR treatment is the TTR tetramer stabilization through the binding of small molecules. These molecules can prevent tetramer misfolding and dissociation, protecting against fibril formation. The thesis work involves the research of new small molecules acting as fibrillogenesis inhibitors. Based on previous studies, new potential inhibitors have been rationally synthesized. The new compounds include fluorenyl-based inhibitors, curcumin analogues and phtalimmide derivatives. Part of the molecules synthesized as well as other potential inhibitors from the same research group have been co-crystallized with TTR. Using the X-ray macromolecular crystallography the crystals have been studied, and the structures obtained allow a better understanding of the interactions within the binding pockets. During the X-ray crystallographic studies it was giving a particular attention at the radiation damage minimization, researching the best use of the crystals.