Synthesis of glycosylated amino acids related to tumor and alpha-dystroglican mucins

• Grant number: 16/24048-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2017
• End date: December 31, 2017
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Vanessa Leiria Campo
• Grantee: Giulia Pompolo Iossi
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 12/19390-0 - Development of mucin glycoconjugates with diagnostic and therapeutic applications in muscular dystrophies and cancer, AP.JP

Abstract

Mucins are highly glycosylated O-glycoproteins that contain repeated motifs in typical tandem, rich is serine (Ser) and threonine (Thr), which represent potential sites for abundant glycosylation. ±-Dystroglycan (±-DG) mucins contain the tetrasaccharidic structural motif Neu5Ac±2-3Gal²1-4GlcNAc²1-2Man±-O-Ser/Thr biosynthesized by specific glycosyltransferases enzymes. Thus, mutations in specific genes that encode such enzymes lead to hypoglycosylation of ±-dystroglycan (±-DG), which lead to serious dystroglycanopathies, besides being involved in the development of epithelial tumors. On the other hand, tumoral mucins, whose structures are quite similar to ±-DG glycoproteins, have abnormal and incomplete glycans, such as ±GalNAc (Tn), Neu5Ac±2-6±GalNAc (STn) and ²Gal1-3±GalNAc (TF), known as Tumor Associated Carbohydrate Antigens (TACAs), which are considered tumor markers of clinical relevance. Therefore, the synthesis of glycoconjugates mimetics of ±-DG and tumor mucins is of great relevance for the elaboration of novel diagnostic and therapeutic strategies towards muscular dystrophies and tumors, such as the assembly of anti-±-DG and anti-TACAs antibodies, and for the development of synthetic anti-tumor vaccines. Considering the high complexity of glycoconjugates mimetics of the cited mucins, the objective of this work proposal is to synthesize the glycosylated amino acids (building blocks) GlcNAc-²1,2-±Man-ThrOH 1 and ²Gal1-3±GalNAc-ThrOH 2, which are key precursors for obtaining ±-DG and tumor mucins glycopeptides. (AU)