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Abstract <p>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-<b>S</b>ynucleinopathy was modeled <b>i</b>n 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&#xa0;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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年5月27日

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  • Marina V. Burak,
  • Nadezhda E. Pukaeva,
  • Victoria S. Kryshkova,
  • Olga A. Kukharskaya,
  • Maya R. Nazdracheva,
  • Sergey A. Pukhov,
  • Kirill A. Rachenkov,
  • Alla V. Stavrovskaya,
  • Vladimir P. Fisenko,
  • Michail S. Kukharsky,
  • Sergei O. Bachurin

摘要

Abstract

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.