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Int. J. Mol. Sci. 2013, 14(3), 5284-5311; doi:10.3390/ijms14035284
Article

Inhibition of Human Transthyretin Aggregation by Non-Steroidal Anti-Inflammatory Compounds: A Structural and Thermodynamic Analysis

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Received: 8 January 2013; in revised form: 5 February 2013 / Accepted: 7 February 2013 / Published: 6 March 2013
(This article belongs to the Special Issue Protein Folding 2015)
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Abstract: Transthyretin (TTR) is a homotetrameric protein that circulates in plasma and cerebral spinal fluid (CSF) whose aggregation into amyloid fibrils has been associated with at least two different amyloid diseases: senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). In SSA aggregates are composed of WT-TTR, while in FAP more than 100 already-described variants have been found in deposits. Until now, TTR-related diseases have been untreatable, although a new drug called Tafamidis has been approved only in Europe to specifically treat V30M patients. Thus, new strategies are still necessary to treat FAP caused by other variants of TTR. TTR has two channels in the dimer interface that bind to the hormone thyroxin and that have been used to accommodate anti-amyloidogenic compounds. These compounds stabilize the tetramers, rendering TTR less amyloidogenic. Here, we investigated the effects of three non-steroidal anti-inflammatory compounds—sulindac (SUL), indomethacin (IND) and lumiracoxib (LUM)—as tetramer stabilizers and aggregation inhibitors. WT-TTR and the very aggressive TTR variant L55P were used as models. These compounds were able to stabilize TTR against high hydrostatic pressure (HHP), increasing the ΔGf by several kcal. They were also effective in inhibiting WT-TTR and L55P acid- or HHP-induced aggregation; in particular, LUM and IND were very effective, inhibiting almost 100% of the aggregation of both proteins under certain conditions. The species formed when aggregation was performed in the presence of these compounds were much less toxic to cells in culture. The crystal structures of WT-TTR bound to the three compounds were solved at high resolution, allowing the identification of the relevant protein:drug interactions. We discuss here the ligand-binding features of LUM, IND and SUL to TTR, emphasizing the critical interactions that render the protein more stable and less amyloidogenic.
Keywords: transthyretin; protein aggregation; high hydrostatic pressure; crystallography; inhibitors transthyretin; protein aggregation; high hydrostatic pressure; crystallography; inhibitors
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Sant'Anna, R.O.; Braga, C.A.; Polikarpov, I.; Ventura, S.; Lima, L.M.T.R.; Foguel, D. Inhibition of Human Transthyretin Aggregation by Non-Steroidal Anti-Inflammatory Compounds: A Structural and Thermodynamic Analysis. Int. J. Mol. Sci. 2013, 14, 5284-5311.

AMA Style

Sant'Anna RO, Braga CA, Polikarpov I, Ventura S, Lima LMTR, Foguel D. Inhibition of Human Transthyretin Aggregation by Non-Steroidal Anti-Inflammatory Compounds: A Structural and Thermodynamic Analysis. International Journal of Molecular Sciences. 2013; 14(3):5284-5311.

Chicago/Turabian Style

Sant'Anna, Ricardo O.; Braga, Carolina A.; Polikarpov, Igor; Ventura, Salvador; Lima, Luis M.T.R.; Foguel, Debora. 2013. "Inhibition of Human Transthyretin Aggregation by Non-Steroidal Anti-Inflammatory Compounds: A Structural and Thermodynamic Analysis." Int. J. Mol. Sci. 14, no. 3: 5284-5311.



Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert