Identification and characterization of UBE2A enzyme modulators by automated high-throughput screening

• Grant number: 24/07830-3
• Support Opportunities: Scholarships in Brazil - Master
• Start date: October 01, 2024
• End date: July 31, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal Investigator: Gustavo Fernando Mercaldi
• Grantee: Jean Rodrigo Santos
• Host Institution: Centro Nacional de Pesquisa em Energia e Materiais (CNPEM). Ministério da Ciência, Tecnologia e Inovação (Brasil). Campinas , SP, Brazil

Abstract

Protein ubiquitination plays a central role in synaptic development and function, regulating processes including protein degradation and cell cycle regulation. Dysfunction of the enzymes involved in this pathway is associated with various pathological conditions, including neurodevelopmental and neurodegenerative diseases such as intellectual disability (DI), Alzheimer's disease and Parkinson's disease. One of these enzymes, UBE2A, a ubiquitin ligase (E2), emerges as a potential therapeutic target, given that dysfunctions in its activity have been linked to the development of DI. Thus, modulation of this enzyme involved in the ubiquitination cascade represents a promising strategy for the development of new therapies. To address this issue, we propose conducting a large-scale automated screening (HTS - high-throughput screening) to identify UBE2A modulators. This approach will allow the evaluation of thousands of chemical compounds to identify specific UBE2A modulators. Following the identification of these modulators, biochemical and biophysical studies will be conducted to elucidate the mechanism of interaction between these molecules and the enzyme. Additionally, in vitro phenotypic and functional assays using human neuroblastoma cells will be employed to evaluate the modulators. Deepening our understanding of the interaction between UBE2A and the identified modulators will not only enhance knowledge about this enzyme's function but also establish a solid foundation for the development of new drugs for patients affected by the dysregulation of the ubiquitination pathway.