A new molecule to fight against transthyretin amyloidosis

IBB-UAB researchers have developed a second-generation molecule that significantly improves the stabilization and aggregation inhibition of the proteins involved in Transthyretin Amyloidosis (ATTR), a group of minority degenerative diseases.

The new molecule, designated as PITB (Pharmacokinetically Improved TTR Binder), results from a series of studies aimed at improving both the activity and the pharmacokinetic profile of Tolcapone, a drug that the same group of researchers proposed in 2016 for the treatment of ATTR and that is currently undergoing Phase 2 clinical trials.

ATTR is a group of diseases caused by the accumulation of amyloid deposits of the transthyretin (TTR) protein. When TTR becomes unstable due to genetic mutations or aging, it forms deposits that can accumulate in various organs of the body, mainly in the heart and in the peripheral nerves.

In two studies recently published in the Journal of Medicinal Chemistry and the European Journal of Medicinal Chemistry, the researchers describe the design and synthesis of PITB and how its structure binds with a much stronger affinity and greater selectivity than Tolcapone to TTR. This enhanced activity extends to both the wild-type TTR protein and the two most common and clinically relevant mutations, namely those associated with familial amyloid polyneuropathy and familial amyloid cardiomyopathy.

The new molecule significantly stabilizes and inhibits the aggregation of TTR, showing an enhanced stabilizing activity in human plasma, especially from individuals affected by familial amyloid polyneuropathy. In addition, the researchers highlight that PITB exhibits excellent pharmacokinetics and oral bioavailability, with no evidence of hepatotoxicity in cell cultures.

Salvador Ventura, professor of Biochemistry and Molecular Biology and head of the Protein Folding and Conformational Diseases group at IBB, points out that "PITB has all the desired characteristics to be one of the most effective drugs in the fight against ATTR, and at a more affordable price than any current alternative".

The researchers are currently seeking additional funding to conduct in vivo efficacy and toxicity testing, as well as formulation studies. Furthermore, they are considering the creation of a spin-off company to advance towards the first clinical trials, which would be carried out at Son Llàtzer and Vall d'Hebron hospitals.

Articles: Pinheiro, F., Pallarès, I., Peccati, F., Sánchez-Morales, A., Varejão, N., Bezerra, F., Ortega-Alarcon, D., Gonzalez, D., Osorio, M., Navarro, S., Velázquez-Campoy, A., Almeida, M., Reverter, D., Busqué, F., Alibés, Ramon., Sodupe M & Ventura, Salvador. (2022). «Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation». Journal of Medicinal Chemistry. 65. 14673-14691. 10.1021/acs.jmedchem.2c01195

Pinheiro, F., Varejão, N., Sánchez-Morales, A., Bezerra, F., Navarro, S., Velázquez-Campoy, A., Busqué, F., Almeida, M., Alibés, R., Reverter, D., Pallarès, I & Ventura, S. (2023). «PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties». European Journal of Medicinal Chemistry. 261. 115837. 10.1016/j.ejmech.2023.115837.