Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans

Amirthalingam Mohankumar; Duraisamy Kalaiselvi; Govindhan Thiruppathi; Sivaramakrishnan Muthusaravanan; Subramaniam Vijayakumar; Rahul Suresh; Shinkichi Tawata; Palanisamy Sundararaj

doi:10.3389/fphar.2022.924862

Santalol Isomers Inhibit Transthyretin Amyloidogenesis and Associated Pathologies in Caenorhabditis elegans

Front Pharmacol. 2022 Jun 16:13:924862. doi: 10.3389/fphar.2022.924862. eCollection 2022.

Authors

Amirthalingam Mohankumar^{1

2}, Duraisamy Kalaiselvi³, Govindhan Thiruppathi², Sivaramakrishnan Muthusaravanan⁴, Subramaniam Vijayakumar⁵, Rahul Suresh⁶, Shinkichi Tawata¹, Palanisamy Sundararaj²

Affiliations

¹ PAK Research Center, University of the Ryukyus, Okinawa, Japan.
² Department of Zoology, Bharathiar University, Coimbatore, India.
³ Department of Agricultural Chemistry, Institute of Environmentally Friendly Agriculture, College of Agriculture and Life Science, Chonnam National University, Gwangju, South Korea.
⁴ Department of Biotechnology, Mepco Schlenk Engineering College, Sivakasi, India.
⁵ Department of Medical Physics, Bharathiar University, Coimbatore, India.
⁶ International Research Center of Spectroscopy and Quantum Chemistry-IRC SQC, Siberian Federal University, Krasnoyarsk, Russia.

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 TTR_WT::EGFP and TTR_V30M::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.