Molecules behind insoluble protein deposits
Familial amyloidosis is a rare inherited condition characterised by the build-up of abnormal deposits of the protein transthyretin (TTR) in various organs. Nearly 100 mutations in the TTR gene are known to cause amyloidosis. Affected individuals show early and severe impairment of the autonomous nervous system and also visual deterioration. TTR is a protein comprising four sub-units (so is tetrameric) found in the serum and cerebrospinal fluid, which acts as a carrier of the thyroid hormone thyroxine. Incorrect folding of TTR leads to formation of insoluble fibrils. The current standard treatment for familial TTR amyloidosis is liver transplantation, while certain small compounds have also demonstrated a stabilising effect on TTR. The EU-funded FIBRILLATION (The structure-based design of a blocker of formation of amyloid fibers of the segment AADTWE in the mutant D38A of the protein transthyretin, which causes familial amyloidosis) consortium proposed a different approach to stop TTR aggregation through the protective binding of specific non-natural peptides to TTR monomers. Scientists analysed different segments of TTR, and demonstrated their capacity to form amyloid fibres. Key to this process was a particular part of the protein known as beta-strand F, which gets exposed in the monomeric form of the protein and can lead to TTR aggregation. Taking advantage of this information, the consortium developed TTR-specific inhibitors that adhere to the strands F and H when TTR is in monomeric form. These inhibitors successfully prevented abnormal folding and aggregation of TTR in vitro. In addition, N-methyl residues were incorporated into the peptide sequence to increase effectiveness. Previous research has shown that non-natural amino acids can increase peptide stability by reducing proteolytic degradation. Results showed that the peptide inhibitors had a synergistic effect suggesting they have separate binding sites via a mechanism not involving protein stabilisation. As a result, these inhibitors did not compete with the addition of a natural ligand T4 and increased the protein's thermostability. To test the potential of this approach as a valid treatment, the next step would involve administering these inhibitors in animal models of the disease. Although preliminary, the FIBRILLATION strategy offers a promising alternative to existing treatments.
Keywords
Amyloidosis, transthyretin, fibril, treatment, beta-strand F, inhibitor
