Sycosterol A, an α-Synuclein Inhibitory Sterol from the Australian Ascidian Sycozoa cerebriformis

During a recent biodiscovery study to identify new alpha-synuclein (alpha-syn) aggregation inhibitors, we screened 29 Australian marine sponge and ascidian extracts in an MS binding assay. This resulted in an extract from the ascidian Sycozoa cerebriformis showing activity toward alpha-syn. The bioassay and MS guided isolation process led to the identification of one new polyoxygenated sterol sulfate, sycosterol A (1). The structure of this low-yielding steroid was elucidated from HRMS and NMR analysis. Sycosterol A displayed moderate antiaggregation activity with 46.2% (+/- 1.8) inhibition when screened against alpha-syn at a 5:1 (sycosterol A:alpha-syn) molar ratio. The alpha-syn antiaggregation activity displayed by 1 and the recent discovery of similar sterols with alpha-syn antiaggregation activity and potent antiprion activity suggest this unique class may be useful antineurodegenerative compounds.

Automated summary

In a biodiscovery study focusing on alpha-synuclein aggregation inhibitors, a new polyoxygenated sterol sulfate named sycosterol A was identified from an Australian ascidian extract and showed moderate antiaggregation activity against alpha-synuclein. This unique class of compounds may have potential as antineurodegenerative agents, given their similar activities to other sterols with antiaggregation properties.