2. Academic Validation
  3. 3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity

3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity

  • Int J Mol Sci. 2023 Dec 29;25(1):479. doi: 10.3390/ijms25010479.
Thanalai Poonsiri 1,  Davide Dell'Accantera 2,  Valentina Loconte 3 4,  Alessandro Casnati 2,  Laura Cervoni 5,  Alessandro Arcovito 6 7,  Stefano Benini 1,  Alberto Ferrari 8,  Marco Cipolloni 9,  Elisa Cacioni 9,  Francesca De Franco 9,  Nicola Giacchè 9,  Serena Rinaldo 5,  Claudia Folli 8,  Francesco Sansone 2,  Rodolfo Berni 2,  Michele Cianci 10
Affiliations

Affiliations

  • 1 Bioorganic Chemistry and Bio-Crystallography Laboratory (B2Cl), Faculty of Agricultural, Environmental and Food Sciences, Free University of Bolzano, 39100 Bolzano, Italy.
  • 2 Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parco Area delle Scienze 17/a, 43124 Parma, Italy.
  • 3 Department of Anatomy, University of California San Francisco, San Francisco, CA 94143, USA.
  • 4 Lawrence Berkeley National Laboratory, Molecular Biophysics and Integrated Bioimaging Division, Berkeley, CA 94720, USA.
  • 5 Department of Biochemical Sciences, University of Rome "La Sapienza", P.le Aldo Moro 5, 00185 Rome, Italy.
  • 6 Department of Biotechnological Sciences and Intensive Care, Catholic University of Sacred Heart, Largo F. Vito 1, 00168 Rome, Italy.
  • 7 Fondazione Policlinico Universitario A. Gemelli-IRCCS, 00168 Rome, Italy.
  • 8 Department of Food and Drug, University of Parma, 43124 Parma, Italy.
  • 9 TES Pharma S.r.l., Via P. Togliatti 20, Corciano, 06073 Perugia, Italy.
  • 10 Department of Agricultural, Food and Environmental Sciences, Università Politecnica delle Marche, Via Brecce Bianche, 60131 Ancona, Italy.
PMID: 38203650 DOI: 10.3390/ijms25010479
Abstract

Transthyretin (TTR) is an amyloidogenic homotetramer involved in the transport of thyroxine in blood and cerebrospinal fluid. To date, more than 130 TTR point mutations are known to destabilise the TTR tetramer, leading to its extracellular pathological aggregation accumulating in several organs, such as heart, peripheral and autonomic nerves, and leptomeninges. Tolcapone is an FDA-approved drug for Parkinson's disease that has been repurposed as a TTR stabiliser. We characterised 3-O-methyltolcapone and two newly synthesized lipophilic analogues, which are expected to be protected from the metabolic glucuronidation that is responsible for the lability of tolcapone in the organism. Immunoblotting assays indicated the high degree of TTR stabilisation, coupled with binding selectivity towards TTR in diluted plasma of 3-O-methyltolcapone and its lipophilic analogues. Furthermore, in vitro toxicity data showed their several-fold improved neuronal and hepatic safety compared to tolcapone. Calorimetric and structural data showed that both T4 binding sites of TTR are occupied by 3-O-methyltolcapone and its lipophilic analogs, consistent with an effective TTR tetramer stabilisation. Moreover, in vitro permeability studies showed that the three compounds can effectively cross the blood-brain barrier, which is a prerequisite for the inhibition of TTR amyloidogenesis in the cerebrospinal fluid. Our data demonstrate the relevance of 3-O-methyltolcapone and its lipophilic analogs as potent inhibitors of TTR amyloidogenesis.

Keywords

amyloidogenesis inhibitors; molecular docking and structure; neuronal and hepatic safety; tolcapone analogues; transthyretin.

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