FROM SPIDER VENOM TO NOVEL INHIBITORS OF AΒ AND Α-SYNUCLEIN AGGREGATION

Spider venoms constitute a rich natural biochemical repertoire. The spider Parawixia bistriata, exhibits intriguing behavioral ecology and produces a diverse arsenal of neuroactive molecules. In this study, venoms from female and male specimens were compared to evaluate their anti-amyloid potential against the pathological αSA53T variant of α-synuclein, a key protein in synucleinopathies. Aggregation kinetics were monitored by Thioflavin T fluorescence, using α-synuclein (10 μM) alone or in the presence of venom at α-synuclein/venom ratios of 1:1, 5:1, and 10:1, in 50 mM phosphate buffer (pH 7.4) at 37°C. Female venom exhibiting greater inhibitory potency, providing the first evidence that spider venoms can modulate pathological α-synuclein aggregation. Given the established pathological and mechanistic overlap between α-synuclein and amyloid-β aggregation pathways in neurodegenerative diseases, further assays were performed with amyloid-β under comparable conditions. Consistently, P. bistriata venom efficiently inhibited amyloid-β aggregation, reinforcing its broad anti-amyloidogenic profile. Based on these findings, bioactive components were isolated and characterized from this venom. RT-HPLC analyses revealed that Parawixin-10 was previously reported by our group as neuroprotective in in vitro excitotoxicity and in vivo epilepsy models, also exhibited potent antifungal activity against Candida glabrata at nM concentrations. Finally, in differentiated SH-SY5Y cells challenged with amyloid-β oligomers (2 μM) and co-treated with Parawixin-10 (50 μM) for 24 hours, oligomer binding was significantly reduced. Collectively, these results underscore the immense potential of natural products as an indispensable source of novel molecules for neurodegenerative disease research and therapeutic innovation.