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

Journal Article · · International Journal of Molecular Sciences (Online)
DOI:https://doi.org/10.3390/ijms25010479· OSTI ID:2470816
 [1];  [2];  [3];  [2];  [4];  [5];  [1];  [2];  [6];  [6];  [6];  [6];  [4];  [2];  [2];  [2];  [7]
  1. Free Univ. of Bolzano (Italy)
  2. Univ. of Parma (Italy)
  3. Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
  4. Univ. of Rome (Italy)
  5. Catholic Univ. of Sacred Heart, Rome (Italy); Fondazione Policlinico Universitario A. Gemelli—IRCCS, Rome (Italy)
  6. TES Pharma S.r.l., Perugia (Italy)
  7. Università Politecnica delle Marche, Ancona (Italy)
+ Show Author Affiliations

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.

Research Organization:
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
2470816
Journal Information:
International Journal of Molecular Sciences (Online), Journal Name: International Journal of Molecular Sciences (Online) Journal Issue: 1 Vol. 25; ISSN IJMCFK; ISSN 1422-0067
Publisher:
MDPICopyright Statement
Country of Publication:
United States
Language:
English

References (67)

Tolcapone and Hepatotoxic Effects journal February 2000
Repurposing Diflunisal for Familial Amyloid Polyneuropathy: A Randomized Clinical Trial journal December 2013
Advances in the treatment of hereditary transthyretin amyloidosis: A review journal August 2019
Tolcapone induces oxidative stress leading to apoptosis and inhibition of tumor growth in Neuroblastoma journal April 2017
FACTS: Fast analytical continuum treatment of solvation journal January 2008
Fast docking using the CHARMM force field with EADock DSS journal May 2011
A comparative analysis of 23 structures of the amyloidogenic protein transthyretin journal September 2000
Transthyretin stability as a key factor in amyloidogenesis: X-ray analysis at atomic resolution journal March 2001
Detection of tolcapone in the cerebrospinal fluid of parkinsonian subjects journal December 1999
Oculoleptomeningeal Amyloidosis associated with transthyretin Leu12Pro in an African patient journal December 2014
Tafamidis: A Review in Transthyretin Amyloidosis with Polyneuropathy journal May 2019
Tolcapone and fulminant hepatitis journal September 1998
High throughput artificial membrane permeability assay for blood–brain barrier journal March 2003
Interactions of tolcapone analogues as stabilizers of the amyloidogenic protein transthyretin journal October 2020
Finding a better path to drug selectivity journal November 2011
A novel bis-furan scaffold for transthyretin stabilization and amyloid inhibition journal October 2016
Systemic optimization and structural evaluation of quinoline derivatives as transthyretin amyloidogenesis inhibitors journal November 2016
Targeting transthyretin in Alzheimer's disease: Drug discovery of small-molecule chaperones as disease-modifying drug candidates for Alzheimer's disease journal December 2021
A new PAMPA model using an in-house brain lipid extract for screening the blood–brain barrier permeability of drug candidates journal March 2016
Distinct characteristics of amyloid deposits in early- and late-onset transthyretin Val30Met familial amyloid polyneuropathy journal December 2009
Structure-activity relationships of flurbiprofen analogues as stabilizers of the amyloidogenic protein transthyretin journal November 2019
Differences in toxicity of the catechol-O-methyl transferase inhibitors, tolcapone and entacapone to cultured human neuroblastoma cells journal March 2004
Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses journal February 2010
Chlorinated Naringenin Analogues as Potential Inhibitors of Transthyretin Amyloidogenesis journal December 2022
Development of a Highly Potent Transthyretin Amyloidogenesis Inhibitor: Design, Synthesis, and Evaluation journal October 2022
Enthalpic Forces Correlate with the Selectivity of Transthyretin-Stabilizing Ligands in Human Plasma journal August 2015
Development of Blood–Brain Barrier Permeable Nitrocatechol-Based Catechol O-Methyltransferase Inhibitors with Reduced Potential for Hepatotoxicity journal August 2016
Enthalpy-Driven Stabilization of Transthyretin by AG10 Mimics a Naturally Occurring Genetic Variant That Protects from Transthyretin Amyloidosis journal August 2018
Brain Permeable Tafamidis Amide Analogs for Stabilizing TTR and Reducing APP Cleavage journal March 2020
Synthesis of 1-(3,4-Dihydroxy-5-nitrophenyl)-2-phenyl-ethanone and Derivatives as Potent and Long-Acting Peripheral Inhibitors of Catechol-O-methyltransferase journal December 2001
Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol- O -methyltransferase journal April 2010
Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity journal February 2016
A molecular mechanism for transthyretin amyloidogenesis journal February 2019
Cryo-EM structure of a transthyretin-derived amyloid fibril from a patient with hereditary ATTR amyloidosis journal November 2019
Hereditary transthyretin amyloidosis: a model of medical progress for a fatal disease journal June 2019
Inhibition of the mechano-enzymatic amyloidogenesis of transthyretin: role of ligand affinity, binding cooperativity and occupancy of the inner channel journal March 2017
Transthyretin amyloidosis: an under-recognized neuropathy and cardiomyopathy journal February 2017
Metabolism and excretion of tolcapone, a novel inhibitor of catechol‐O‐methyltransferase journal October 1999
Oligonucleotide Drugs for Transthyretin Amyloidosis journal July 2018
Tafamidis, a potent and selective transthyretin kinetic stabilizer that inhibits the amyloid cascade journal May 2012
AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin journal May 2013
Sequence-dependent denaturation energetics: A major determinant in amyloid disease diversity journal December 2002
Amyloidogenic Potential of Transthyretin Variants journal September 2009
Transthyretin Binding Heterogeneity and Anti-amyloidogenic Activity of Natural Polyphenols and Their Metabolites journal December 2015
R104H may suppress transthyretin amyloidogenesis by thermodynamic stabilization, but not by the kinetic mechanism characterizing T119 interallelic trans-suppression journal January 2006
Early intervention with tafamidis provides long-term (5.5-year) delay of neurologic progression in transthyretin hereditary amyloid polyneuropathy journal July 2016
Tafamidis delays disease progression in patients with early stage transthyretin familial amyloid polyneuropathy: additional supportive analyses from the pivotal trial journal January 2017
Natural compounds as inhibitors of transthyretin amyloidosis and neuroprotective agents: analysis of structural data for future drug design journal January 2020
SwissDock, a protein-small molecule docking web service based on EADock DSS journal May 2011
Current Review of Leptomeningeal Amyloidosis Associated With Transthyretin Mutations journal September 2021
Scaling and assessment of data quality journal December 2005
MrBUMP : an automated pipeline for molecular replacement journal December 2007
XDS journal January 2010
PHENIX: a comprehensive Python-based system for macromolecular structure solution journal January 2010
Features and development of Coot journal March 2010
Structures of Human Transthyretin Complexed with Thyroxine at 2.0 Å Resolution and 3',5'-Dinitro-N-acetyl-L-thyronine at 2.2 Å Resolution journal July 1996
P13, the EMBL macromolecular crystallography beamline at the low-emittance PETRA III ring for high- and low-energy phasing with variable beam focusing journal January 2017
Binding site asymmetry in human transthyretin: insights from a joint neutron and X-ray crystallographic analysis using perdeuterated protein journal October 2014
Tolcapone, a potent aggregation inhibitor for the treatment of familial leptomeningeal amyloidosis journal May 2020
Docking, virtual high throughput screening and in silico fragment‐based drug design journal February 2009
Changes in pathological and biochemical findings of systemic tissue sites in familial amyloid polyneuropathy more than 10 years after liver transplantation journal September 2013
CNS involvement in V30M transthyretin amyloidosis: clinical, neuropathological and biochemical findings journal August 2014
Treatment With Tafamidis Slows Disease Progression in Early-Stage Transthyretin Cardiomyopathy journal January 2017
THAOS – The Transthyretin Amyloidosis Outcomes Survey: initial report on clinical manifestations in patients with hereditary and wild-type transthyretin amyloidosis journal December 2012
Modifications of the 7-Hydroxyl Group of the Transthyretin Ligand Luteolin Provide Mechanistic Insights into Its Binding Properties and High Plasma Specificity journal April 2016
Patisiran, an RNAi Therapeutic for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis journal November 2018
Chemical Constituents of the Ethyl Acetate Extract from Diaphragma juglandis Fructus and Their Inhibitory Activity on Nitric Oxide Production In Vitro journal December 2017

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Related Subjects

59 BASIC BIOLOGICAL SCIENCES
amyloidogenesis inhibitors
molecular docking and structure
neuronal and hepatic safety
tolcapone analogues
transthyretin