Objective: This study identifies marine-derived natural products with binding affinity and aggregation-inhibition activity against α-synuclein (α-syn) using a mass spectrometry (MS)-based screening approach. The objective was to isolate and identify compounds that selectively bind α-syn and/or inhibit its aggregation, offering insights into their mechanism of action and therapeutic potential.

Background: Parkinson’s disease (PD) holds a significantly unmet medical need, with current treatments offering only symptomatic relief and no neuroprotective options.¹  Small-molecule therapies are preferred due to the challenges protein-based drugs face, such as crossing the blood-brain barrier and triggering immune responses.^2-4 Natural products are promising candidates due to their affinity for α-syn and other amyloid proteins, and their ability to inhibit aggregation, a critical early event in PD progression.⁵ Targeting these early stages of aggregation has become a novel approach that could lead us to neuroprotective therapies.⁶

Method: Here, a mass spectrometry-based assay was employed to evaluate the α-syn binding activity of a diverse library of subtropical marine invertebrate extracts.⁶ The assay detects shifts in the m/z ratio of α-syn caused by both covalent and non-covalent interactions with small molecules. Extracts were screened to identify those exhibiting binding affinity to the protein, and secondary analyses were conducted to assess aggregation inhibition properties.

Results: This resulted in the isolation of several marine natural products that demonstrated significant α-syn binding affinity. Further characterization indicated that specific compounds exhibited pronounced aggregation-inhibition activity as well.^7-11 These findings highlight the potential of marine natural products as a rich source of lead compounds for PD drug development.

Conclusion: Overall, marine-derived natural products represent an untapped resource for discovering novel therapeutics targeting α-syn misfolding and aggregation.^12-14 The use of MS as a high-throughput screening tool offers a powerful platform for identifying α-syn binders, accelerating drug discovery efforts, and providing valuable insights into α-syn structural and functional aspects beyond protein aggregation.

References: (1) LeWitt, P. A.; Chaudhuri, K. R. Unmet needs in Parkinson disease: Motor and non-motor. Parkinsonism & Related Disorders 2020, 80, S7-S12.
(2) Jena, D.; Srivastava, N.; Chauhan, I.; Verma, M. Challenges and Therapeutic Approaches for the Protein Delivery System: A Review. Pharmaceutical Nanotechnology 2024, 12 (5), 391-411.
(3) Zhang, H.; Tong, R.; Bai, L.; Shi, J.; Ouyang, L. Emerging targets and new small molecule therapies in Parkinson’s disease treatment. Bioorganic & medicinal chemistry 2016, 24 (7), 1419-1430.
(4) Pérez-Arancibia, R.; Cisternas-Olmedo, M.; Sepúlveda, D.; Troncoso-Escudero, P.; Vidal, R. L. Small molecules to perform big roles: The search for Parkinson’s and Huntington’s disease therapeutics. Frontiers in Neuroscience 2023, 16, 1084493.
(5) Atanasov, A. G.; Zotchev, S. B.; Dirsch, V. M.; Supuran, C. T. Natural products in drug discovery: advances and opportunities. Nature reviews Drug discovery 2021, 20 (3), 200-216.
(6) Xu, M.; Loa-Kum-Cheung, W.; Zhang, H.; Quinn, R. J.; Mellick, G. D. Identification of a new α-synuclein aggregation inhibitor via mass spectrometry based screening. ACS Chemical Neuroscience 2019, 10 (6), 2683-2691.
(7) Prebble, D. W.; Xu, M.; Mellick, G. D.; Carroll, A. R. Sycosterol a, an α-synuclein inhibitory sterol from the Australian ascidian Sycozoa cerebriformis. Journal of Natural Products 2021, 84 (12), 3039-3043.
(8) Prebble, D. W.; Holland, D. C.; Hayton, J. B.; Ferretti, F.; Jennings, L. K.; Everson, J.; Xu, M.; Kiefel, M. J.; Mellick, G. D.; Carroll, A. R. α-Synuclein aggregation inhibitory Procerolides and diphenylalkanes from the ascidian Polycarpa procera. Journal of Natural Products 2023, 86 (3), 533-540.
(9) Prebble, D. W.; Er, S.; Xu, M.; Hlushchuk, I.; Domanskyi, A.; Airavaara, M.; Ekins, M. G.; Mellick, G. D.; Carroll, A. R. α-synuclein aggregation inhibitory activity of the bromotyrosine derivatives aerothionin and aerophobin-2 from the subtropical marine sponge Aplysinella sp. Results in chemistry 2022, 4, 100472.
(10) Jennings, L. K.; Prebble, D. W.; Xu, M.; Ekins, M. G.; Munn, A. L.; Mellick, G. D.; Carroll, A. R. Anti-prion and α-Synuclein Aggregation Inhibitory Sterols from the Sponge Lamellodysidea cf. chlorea. Journal of Natural Products 2020, 83 (12), 3751-3757.
(11) Holland, D. C.; Prebble, D. W.; Er, S.; Hayton, J. B.; Robertson, L. P.; Avery, V. M.; Domanskyi, A.; Kiefel, M. J.; Hooper, J. N.; Carroll, A. R. α-Synuclein aggregation inhibitory prunolides and a dibrominated β-carboline sulfamate from the ascidian Synoicum prunum. Journal of Natural Products 2022, 85 (2), 441-452.
(12) Molinski, T. F.; Dalisay, D. S.; Lievens, S. L.; Saludes, J. P. Drug development from marine natural products. Nature reviews Drug discovery 2009, 8 (1), 69-85.
(13) Villa, F. A.; Gerwick, L. Marine natural product drug discovery: Leads for treatment of inflammation, cancer, infections, and neurological disorders. Immunopharmacology and immunotoxicology 2010, 32 (2), 228-237.
(14) Altmann, K.-H. Drugs from the oceans: Marine natural products as leads for drug discovery. Chimia 2017, 71 (10), 646-646.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/mass-spectrometry-based-screening-for-%ce%b1-synuclein-bioactive-marine-natural-products/