A Conjugate of Aminoadamantane and Tetrahydro-γ-Carboline Inhibits Accumulation of Mutant α-Synuclein A53T in the Cellular Model of Proteinopathy

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Marina V. Burak¹, Nadezhda E. Pukaeva¹, Victoria S. Kryshkova¹, Olga A. Kukharskaya¹, Maya R. Nazdracheva¹, Sergey A. Pukhov¹, Kirill A. Rachenkov¹, Alla V. Stavrovskaya², Vladimir P. Fisenko³, Michail S. Kukharsky^1,a*, and Sergei O. Bachurin^1,b*

¹Institute of Physiologically Active Compounds, Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, 142432 Chernogolovka, Moscow Region, Russia

²Russian Center of Neurology and Neurosciences, Ministry of Science and Higher Education of the Russian Federation, 125367 Moscow, Russia

³First Moscow State Medical University (Sechenov University), Ministry of Health of the Russian Federation, 119048 Moscow, Russia

^* To whom correspondence should be addressed.

Received: January 14, 2026; Revised: March 10, 2026; Accepted: March 11, 2026

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Pathological aggregation of α-synuclein is a key event in the development of synucleinopathies, such as Parkinson’s disease and Lewy body dementia. Currently, no effective disease-modifying therapy is available, necessitating the search for new therapeutic agents. One promising strategy involves the use of low-molecular-weight compounds capable of inhibiting the formation of toxic protein aggregates. This study evaluates the anti-aggregation properties of EC3222x, a conjugate of pharmacophoric fragments of amantadine and a fluorinated derivative of tetrahydro-γ-carboline. α-Synucleinopathy was modeled in the SH-SY5Y neuroblastoma cell line by transfection with a plasmid vector encoding the mutant human α-synuclein A53T protein. EC3222x at a concentration of 1 µM reduced the number of cells with α-synuclein A53T aggregates. Its efficacy was comparable to that of SynuClean-D and Buntanetap, known inhibitors of α-synuclein aggregation. Treatment with EC3222x reduced both the level of diffusely distributed intracellular α-synuclein and the formation of mature fibrillar aggregates and large aggresomes. Importantly, EC3222x did not affect the accumulation of another aggregation-prone protein, TDP-43, in a similar cellular model, indicating its specificity for α-synuclein. These findings suggest that EC3222x may represent a promising candidate for the development of therapeutic agents targeting synucleinopathies.

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KEY WORDS: protein aggregation, α-synuclein, neurodegenerative diseases, cellular models, protein aggregation inhibitors, neuroprotective agents

DOI: 10.1134/S0006297926600079

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