PITB : A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties
Pinheiro, Francisca (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Varejão, Nathalia (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Sánchez-Morales, Adrià (Universitat Autònoma de Barcelona. Departament de Química)
Bezerra, Filipa (Instituto de Ciências Biomédicas de Abel Salazar (Porto, Portugal))
Navarro, Susanna (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Velázquez-Campoy, Adrian (Universidad de Zaragoza)
Busqué Sánchez, Félix (Universitat Autònoma de Barcelona. Departament de Química)
Almeida, Maria Rosário (Instituto de Ciências Biomédicas de Abel Salazar (Porto, Portugal))
Alibes, Ramón (Universitat Autònoma de Barcelona. Departament de Química)
Reverter i Cendrós, David (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Pallarès i Goitiz, Irantzu (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Ventura, Salvador (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)

Date:	2023
Abstract:	The aggregation of wild-type transthyretin (TTR) and over 130 genetic TTR variants underlies a group of lethal disorders named TTR amyloidosis (ATTR). TTR chemical chaperones are molecules that hold great promise to modify the course of ATTR progression. In previous studies, we combined rational design and molecular dynamics simulations to generate a series of TTR selective kinetic stabilizers displaying exceptionally high affinities. In an effort to endorse the previously developed molecules with optimal pharmacokinetic properties, we conducted structural design optimization, leading to the development of PITB. PITB binds with high affinity to TTR, effectively inhibiting tetramer dissociation and aggregation of both the wild-type protein and the two most prevalent disease-associated TTR variants. Importantly, PITB selectively binds and stabilizes TTR in plasma, outperforming tolcapone, a drug currently undergoing clinical trials for ATTR. Pharmacokinetic studies conducted on mice confirmed that PITB exhibits encouraging pharmacokinetic properties, as originally intended. Furthermore, PITB demonstrates excellent oral bioavailability and lack of toxicity. These combined attributes position PITB as a lead compound for future clinical trials as a disease-modifying therapy for ATTR.
Grants:	Agencia Estatal de Investigación PID2019-106403RB-I00
Note:	Altres ajuts: acords transformatius de la UAB
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Amyloidosis ; Lead optimization ; Pharmacokinetics ; Stabilizers ; Transthyretin ; V30M
Published in:	European Journal of Medicinal Chemistry, Vol. 261 (may 2023) , p. 115837, ISSN 1768-3254

DOI: 10.1016/j.ejmech.2023.115837
PMID: 37837673

10 p, 5.6 MB

The record appears in these collections:
Research literature > UAB research groups literature > Research Centres and Groups (research output) > Experimental sciences > Synthesis of Bioactive Organic Compounds and Functional Materials (SynOrgFUN)
Articles > Research articles
Articles > Published articles