(534d) A New Class of Compounds Inhibiting the Amyloidosis of TTR(105-115): Insights from Experiments and Molecular Dynamics Simulations Conference: AIChE Annual MeetingYear: 2015Proceeding: 2015 AIChE Annual MeetingGroup: Food, Pharmaceutical & Bioengineering DivisionSession: Fundamentals of Protein Folding in Diseases Time: Wednesday, November 11, 2015 - 2:00pm-2:20pm Authors: Tamamis, P., TAMU Christophi, N., University of Cyprus Pepi, P., Berezin, A. A., University of Cyprus Zissimou, G. A., Koutentis, P. A., Hayes, S. C., Palughi, A. J., Artie Mc Human transthyretin (TTR) is among the key proteins involved in serious amyloid diseases. It is a cerebrospinal fluid and serum protein, produced by the liver, which, in its regular function, transports thyroxin and retinol-binding protein. The misfolded mutants of this protein are involved in familial amyloid polyneuropathy (FAP), senile cardiac amyloidosis (SCA), and senile systemic amyloidosis (SSA), all very serious diseases [1,2,3,4]. A major class of inhibitors of TTR amyloidosis bind to the thyroxine (T4) binding pocket and interact specifically with a section of the TTR sequence, corresponding to residues 105−115, that is implicated in amyloidogenic propensity. The findings of a recent experimental study suggest that “stabilizing” inhibitors of the TTR 105-115 amyloidosis, may also directly disrupt amyloidogenic aggregation of TTR monomers through specific interactions with the exposed TTR (105−115) sequence . Thus the discovery of novel inhibitors of amyloidosis by TTR 105-115 peptide fragments appears a promising direction for developing future therapeutics for diseases associated with the entire TTR protein. In this work, we discovered a new class of molecules inhibiting the aggregation of TTR(105−115) peptides. A series of Resonance Raman and fluorescence studies were performed to investigate the inhibition effect through specific interactions of these molecules with the peptide. Replica Exchange Molecular Dynamics (REMD) simulations were introduced to provide further insights into the inhibition mechanism of the novel compounds. Our results reveal that the presence of inhibiting compounds in solution with TTR(105−115) peptides disfavors the formation of β-sheet structures of high complexity that can serve as structural units promoting the amyloid formation. We delineate the functional role of each group of the inhibitor with regard to the formation of interactions with TTR(105−115) peptides, and provide a comparison with existing molecules targeting the TTR(105−115) fragment and inhibiting the amyloid formation of the entire TTR protein. Our study offers significant insights for the design of novel molecules which can specifically target TTR(105−115) peptides and inhibit their amyloidosis, and can also potentially inhibit the amyloidosis of the entire TTR protein. References 1. Lee KW, Lee DH, Son H, Kim YS, Park JY, Roh GS, Kim, HJ, Kang SS, Cho GJ, Choi WS. (2009) Clusterin regulates transthyretin amyloidosis. Biochem Biophys Res Commun 388:256−260. 2. Ando Y, Nakamura M, Araki S. (2005) Transthyretinrelated familial amyloidotic polyneuropathy. Arch Neurol 62: 1057−1062. 3. Pieridou G, Avgousti-Menelaou C, Tamamis P, Archontis G, Hayes SC. (2011) UV resonance Raman study of TTR(105-115) structural evolution as a function of temperature. J Phys Chem B. 115: 4088-4098. 4. Liang Y, Ore MO, Morin S, Wilson DJ. (2012) Specific disruption of transthyretin(105-115) fibrilization using "stabilizing" inhibitors of transthyretin amyloidogenesis. Biochemistry 51: 3523-3530.