2. Academic Validation
  3. PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties

PITB: A high affinity transthyretin aggregation inhibitor with optimal pharmacokinetic properties

  • Eur J Med Chem. 2023 Oct 6:261:115837. doi: 10.1016/j.ejmech.2023.115837.
Francisca Pinheiro 1,  Nathalia Varejão 1,  Adrià Sánchez-Morales 2,  Filipa Bezerra 3,  Susanna Navarro 1,  Adrián Velázquez-Campoy 4,  Félix Busqué 2,  Maria Rosário Almeida 3,  Ramon Alibés 2,  David Reverter 1,  Irantzu Pallarès 5,  Salvador Ventura 6
Affiliations

Affiliations

  • 1 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain.
  • 2 Departament de Química, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain.
  • 3 Molecular Neurobiology Group, i3S - Instituto de Investigação e Inovação em Saúde, IBMC - Instituto de Biologia Molecular e Celular, Universidade do Porto, 4200-135, Porto, Portugal; Departamento de Biologia Molecular, ICBAS - Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313, Porto, Portugal.
  • 4 Department of Biochemistry and Molecular & Cellular Biology, and Institute for Biocomputation and Physics of Complex Systems (BIFI), Joint Unit GBsC-CSIC-BIFI, Universidad de Zaragoza, Zaragoza, Spain; Aragon Institute for Health Research, Zaragoza (Spain) and Biomedical Research Network Center in Hepatic and Digestive Diseases (CIBERehd), Madrid, Spain.
  • 5 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain. Electronic address: [email protected].
  • 6 Institut de Biotecnologia i Biomedicina and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, 08193, Spain; ICREA, Passeig Lluis Companys 23, E-08010, Barcelona, Spain. Electronic address: [email protected].
PMID: 37837673 DOI: 10.1016/j.ejmech.2023.115837
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.

Keywords

Amyloidosis; Lead optimization; Pharmacokinetics; Stabilizers; Transthyretin; V30M.

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