2. Academic Validation
  3. Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis

Design and Mechanistic Analysis of a Potent Bivalent Inhibitor of Transthyretin Amyloid Fibrillogenesis

  • J Med Chem. 2025 Jun 12;68(11):11543-11571. doi: 10.1021/acs.jmedchem.5c00430.
P Patrizia Mangione 1 2,  Guglielmo Verona 1 3,  Cristina Cantarutti 4,  Paola Nocerino 1,  Maria Chiara Mimmi 5,  Christopher J Swain 6,  Diana Canetti 3,  Sofia Giorgetti 1 2,  Iain Uings 7,  Julian D Gillmore 3,  Graham W Taylor 3 8,  Mark B Pepys 8,  Vittorio Bellotti 1 2,  Alessandra Corazza 4 9
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, University of Pavia, 27100 Pavia, Italy.
  • 2 Research Department, Fondazione IRCSS Policlinico San Matteo, 27100 Pavia, Italy.
  • 3 Centre for Amyloidosis, University College London, NW3 2PF London, U.K.
  • 4 Department of Medicine, University of Udine, 33100 Udine, Italy.
  • 5 Transplant Research Area and Centre for Inherited Cardiovascular Diseases, Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy.
  • 6 Cambridge MedChem Consulting, CB22 4RN Cambridge, U.K.
  • 7 GSK Medicines Research Centre, SG1 2NY Stevenage, U.K.
  • 8 Wolfson Drug Discovery Unit, University College London, London NW3 2PF, U.K.
  • 9 Istituto Nazionale Biostrutture e Biosistemi, 00136 Rome, Italy.
PMID: 40421796 DOI: 10.1021/acs.jmedchem.5c00430
Abstract

Transthyretin amyloidosis (ATTR) is a systemic disease that primarily affects the heart and the peripheral nervous system. Despite available therapeutic options, advanced ATTR amyloidosis still presents unmet medical needs. We have therefore focused on the design of bivalent small molecules starting from our prototype palindromic ligand mds84, whose binding by transthyretin (TTR) greatly improves stability of the native structure by overcoming the negative cooperativity which is typical of monovalent stabilizers. Among the newly designed compounds here, we present B26, which is pseudoirreversibly bound by native TTR with faster entry kinetics into the protein molecule compared to mds84. It retains the ability to inhibit fibril formation in vitro, together with improved solubility. Using solution NMR, we show that B26 occupies both TTR binding sites simultaneously, leading to conformational effects distant from the binding site, including the proteolytic cleavage site involved in fibril formation by the mechano-enzymatic mechanism.

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