Alice Fossati
| Identification of Natural Tyrosinase Inhibitors as potential therapy for Neurodegenerative Diseases. |
| Fossati Alice1,2, Cavalloro Valeria1,2, Emanuela Martino1,2, Battisti Verena3, Langer Thierry3, and Collina Simona4. 1 Department of Earth and Environmental Sciences, University of Pavia, Via Ferrata 1, 27100 Pavia, Italy 2 National Biodiversity Future Center, Piazza Marina 61, 90133 Palermo, Italy 3 Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14 (UZA II), 1090 Vienna, Austria 4 Department of Drug Science, University of Pavia, Via Taramelli 12, 27100 Pavia, Italy. |
| Abstract Background: Neurodegenerative diseases (ND) cause progressive neuron loss with severe cognitive/motor deficits. In 2019 they affected 50M people (WHO), rising to 3.4B (43% global population) by 2021. These disorders were responsible for about 11.1 million deaths, making them the leading cause of global disease burden [1]. Tyrosinase (Tyr), known for skin hyperpigmentation, plays a critical role in neurodegeneration: it oxidizes dopamine in dopaminergic neurons, generating reactive intermediates, cytotoxic neuromelanin, and oxidative stress, causative of α-synuclein misfolding, mitochondrial dysfunction, and neuronal apoptosis. Moreover, Tyr overexpression in aging/stress amplifies pathological cascades [2]. Tyr inhibitors are approved only for cosmetic purposes and currently their application as neurodegeneration therapies is currently underrated. In this context, plants produce secondary metabolites with multi-target neuroprotective effects, long used in traditional medicine and now promising for ND prevention. Moreover, no systematic studies exist on human-specific Tyr inhibitors from local flora. Methods: This study aimed to identify natural products with potential therapeutic benefits for ND. In particular, twenty-seven plants belonging to different botanical families were selected using a taxonomic approach within the NBFC project framework and screened in vitro for tyrosinase inhibition [3]. Carissa macrocarpa (Eckl.) A.DC. and Adenophora lilifolia (L.) Ledeb. ex A.DC. extracts demonstrated the most promising inhibitory activity. A comprehensive database of secondary metabolites from these plants was built based on literature and UHPLC-MS phytochemical characterization data. A pharmacophoric model for Tyr inhibitors was developed and validated to screen this database. The resulting hits were subjected to molecular docking analysis towards binding pockets of both Agaricus bisporus (J.E. Lange) Imbach tyrosinase and a human homology model of tyrosinase. Conclusions: Our findings establish a starting point for identifying specific natural products that effectively inhibit Tyr, enabling the preparation of plant extract and isolation of pure compounds with potentially enhanced efficacy against ND diseases. |
| References [1] Maher C, and Ferreira G. Time to reconsider what Global Burden of Disease studies really tell us about low back pain. Ann Rheum Dis. 2022;81:306–8. https://doi.org/10.1136/annrheumdis-2021-221173 [2] Carballo-Carbajal I, Laguna A, Romero-Giménez J, Cuadros T, Bové J, Martinez-Vicente M, et al. Brain tyrosinase overexpression implicates age-dependent neuromelanin production in Parkinson’s disease pathogenesis. Nat Commun. 2019;10:973. https://doi.org/10.1038/s41467-019-08858-y [3] Fossati, A., Cavalloro, V., Negri, S. Linciano P., Guzzo F., Collina S., and Martino E. Bioprospecting Italian biodiversity for identifying potential neuroprotective agents. Sci Rep 2026. https://doi.org/10.1038/s41598-026-47845-4 |