8C86

Crystal structure of human transthyretin in complex with 3-O-methyltolcapone analogue 2

Summary for 8C86

• Entry DOI: 10.2210/pdb8c86/pdb
• Related: 6SUH
• Descriptor: Transthyretin, (2,4-dimethylphenyl)-(3-methoxy-5-nitro-4-oxidanyl-phenyl)methanone (3 entities in total)
• Functional Keywords: amyloidosis, tetramer, binding protein, transport protein, lipid binding protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 28159.32

Authors

Poonsiri, T.,Benini, S.,Loconte, V.,Cianci, M. (deposition date: 2023-01-18, release date: 2024-01-17, Last modification date: 2024-01-24)

Primary citation

Poonsiri, T.,Dell'Accantera, D.,Loconte, V.,Casnati, A.,Cervoni, L.,Arcovito, A.,Benini, S.,Ferrari, A.,Cipolloni, M.,Cacioni, E.,De Franco, F.,Giacche, N.,Rinaldo, S.,Folli, C.,Sansone, F.,Berni, R.,Cianci, M.
3-O-Methyltolcapone and Its Lipophilic Analogues Are Potent Inhibitors of Transthyretin Amyloidogenesis with High Permeability and Low Toxicity.
Int J Mol Sci, 25:-, 2023

PubMed 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.

PubMed: 38203650
DOI: 10.3390/ijms25010479

Experimental method

X-RAY DIFFRACTION (1.1 Å)