ORCID

Abstract

Transthyretin (TTR) is a homotetrameric protein found in human serum and is implicated in fatal inherited amyloidoses. Destabilization of native TTR confirmation resulting from mutation, environmental changes, and aging causes polymerization and amyloid fibril formation. Although several small molecules have been reported to stabilize the native state and inhibit TTR aggregation, prolonged use can cause serious side effects. Therefore, pharmacologically enhancing the degradation of TTR aggregates and kinetically stabilizing the native tetrameric structure with bioactive molecule(s) could be a viable therapeutic strategy to hinder the advancement of TTR amyloidoses. In this context, here we demonstrated α- and β-santalol, natural sesquiterpenes from sandalwood, as a potent TTR aggregation inhibitor and native state stabilizer using combined in vitro, in silico, and in vivo experiments. We found that α- and β-santalol synergize to reduce wild-type (WT) and Val30Met (V30M) mutant TTR aggregates in novel C. elegans strains expressing TTR fragments fused with a green fluorescent protein in body wall muscle cells. α- and β-Santalol extend the lifespan and healthspan of C. elegans strains carrying TTRWT::EGFP and TTRV30M::EGFP transgene by activating the SKN-1/Nrf2, autophagy, and proteasome. Moreover, α- and β-santalol directly interacted with TTR and reduced the flexibility of the thyroxine-binding cavity and homotetramer interface, which in turn increases stability and prevents the dissociation of the TTR tetramer. These data indicate that α- and β-santalol are the strong natural therapeutic intervention against TTR-associated amyloid diseases.

Keywords

Caenorhabditis elegans, familial amyloid polyneuropathy, santalol isomers, synergism, tetramer stabilizer, transthyretin

Publication Date

2022-06-16

Publication Title

Frontiers in Pharmacology

Volume

13

Deposit Date

2026-07-29

Funding

This study was supported in part by Santalis Pharmaceuticals Inc. (San Antonio, TX, United States), who also provided some reagents used in the experiments. We thank Prof. Kunitoshi Yamanaka (Department of Molecular Cell Biology, Kumamoto University, Japan) for providing us with TTR C. elegans strains. Some strains were provided by the Caenorhabditis Genetic Centre (CGC, University of Minnesota, MN, United States), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). Special thanks go to Prof. Julie Ahringer (The Gurdon Institute, University of Cambridge, United Kingdom) for providing us with the RNAi clones. This study was supported in part by Santalis Pharmaceuticals Inc. (San Antonio, TX, United States), who also provided some reagents used in the experiments. We thank Prof. Kunitoshi Yamanaka (Department of Molecular Cell Biology, Kumamoto University, Japan) for providing us with TTR C. elegans strains. Some strains were provided by the Caenorhabditis Genetic Centre (CGC, University of Minnesota, MN, United States), which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). Special thanks go to Prof. Julie Ahringer (The Gurdon Institute, University of Cambridge, United Kingdom) for providing us with the RNAi clones.

Creative Commons License

Creative Commons Attribution 4.0 International License
This work is licensed under a Creative Commons Attribution 4.0 International License.

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