Artificial intelligence-driven drug repositioning uncovers efavirenz as a modulator of α-synuclein propagation: Implications in Parkinson’s disease - 27/04/24
Abstract |
Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.
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Graphical abstract was created with BioRender.com (License number VL26K10Z1Q)El texto completo de este artículo está disponible en PDF.
Highlights |
• | Our AI analysis shows that efavirenz and nevirapine, used in HIV treatment, may impact PD pathophysiology. |
• | In vivo and in vitro, efavirenz attenuates α-syn propagation, micro/astrogliosis, and inhibits α-syn release and uptake. |
• | RNA-seq analysis shows efavirenz modulates cholesterol metabolism, mitigating α-syn propagation in PD via CYP46A1 regulation. |
Keywords : Parkinson’s disease, α-synuclein, Drug repositioning, Efavirenz
Esquema
Vol 174
Artículo 116442- mai 2024 Regresar al númeroBienvenido a EM-consulte, la referencia de los profesionales de la salud.
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