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Developing a comprehensive solution aimed to disrupt LARS1/RagD protein-protein interaction.

Alexey Raevsky1,2,3, Oksana Kovalenko1, Elijah Bulgakov2

  • 1Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine.

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Summary

This study identifies compounds to block leucyl-tRNA synthetase (LARS1) and mTORC1 signaling, offering new cancer therapies that overcome rapamycin resistance.

Keywords:
AlphaFoldLARS1leucyl-tRNA synthetasemTORC1 signalingrapamycinresistance

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cellular Physiology

Background:

  • Aminoacyl-tRNA synthetases are vital enzymes in protein synthesis.
  • Leucyl-tRNA synthetase (LARS1) regulates mTORC1 signaling, impacting cell growth and disease.
  • mTORC1 pathway dysregulation is linked to cancer, obesity, diabetes, and neurodegeneration.

Purpose of the Study:

  • To investigate structural requirements for inhibiting LARS1-mTORC1 signaling.
  • To develop novel chemotherapeutic agents targeting mTORC1.
  • To overcome resistance to existing rapamycin treatments.

Main Methods:

  • In-silico approaches were used to model LARS1-mTORC1 interactions.
  • An alternative interaction model was developed and validated.
  • Compounds were identified for potential therapeutic use.

Main Results:

  • An alternative interaction model for LARS1 and mTORC1 was successfully generated and validated.
  • A set of novel compounds capable of preventing LARS1/RagD interactions were identified.
  • The study provides a foundation for new mTORC1-targeted cancer therapies.

Conclusions:

  • Inhibiting LARS1-mTORC1 signaling is a viable strategy for cancer therapy.
  • The identified compounds show promise in overcoming rapamycin resistance.
  • This research lays the groundwork for developing next-generation mTORC1 inhibitors.