Scholarship 23/13763-4 - Anemia falciforme, Drogas em investigação - BV FAPESP
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Synthesis of new PROTAC compounds aiming to degradate HDAC-1 and -2 for Sickle Cell Disease

Grant number: 23/13763-4
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Start date until: March 01, 2024
End date until: February 28, 2025
Field of knowledge:Health Sciences - Pharmacy
Principal Investigator:Jean Leandro dos Santos
Grantee:Ana Lydssen da Silva Neves Nunes
Host Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

Sickle cell disease (SCD) stands as one of the genetic hematological conditions identified by a point mutation in the beta globin gene. In Brazil, approximately 3,500 individuals are born with SCD annually, and 300,000 carry the sickle cell trait. While there have been advancements in potential curative methods such as allogeneic hematopoietic stem cell transplantation and gene editing, cost and risk associated with these procedures continue to pose significant challenges. Presently, four drugs have received approval from the Food and Drug Administration (FDA) for SCD treatment: hydroxyurea, L-glutamine, voxelotor, and the monoclonal antibody crizanlizumab. The latter three were approved after 2017. Among these, only Hydroxyurea has demonstrated the ability to raise fetal hemoglobin (HbF) levels, a proven and effective strategy in alleviating patient morbidity and mortality. However, due to adverse effects and inadequate responses in some patients, there is an urgent need to explore novel drugs with distinct mechanisms of action for HbF level enhancement. Gamma-globin gene regulation on chromosome 11 involves repressive complexes and enzymes linked to epigenetic processes, such as histone deacetylase (HDAC). Inhibiting HDACs 1 and 2 has shown promise in increasing gamma-globin expression and HbF production, making it a potential target for SCD treatment. Proteolysis Target Chimera (PROTAC) technology is an innovative approach for the specific degradation of enzymes. It operates by simultaneously anchoring the target protein and the E3 ligase enzyme, leading to ubiquitination and subsequent degradation of the protein of interest. Surprisingly, the use of PROTACs in the context of AF treatment remains unexplored. As a result, this project aims to synthesize new PROTACs designed for the degradation of HDACs 1 and 2. This approach represents a novel strategy for inducing gamma-globin expression and HbF production, offering a potentially groundbreaking avenue for SCD treatment.

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