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

• Grant number: 14/23280-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: January 01, 2015
• End date: December 31, 2015
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Vanessa Leiria Campo
• Grantee: Marcelo Fiori Marchiori
• 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 in serine (Ser) and threonine (Thr), which represent potential sites for abundant glycosylation. Alpha-Dystroglycan (alpha-DG) mucins contain the tetrasaccharidic structural motif Neu5Acalpha2-3Galbeta1-4GlcNAcbeta1-2Manalpha-O-Ser/Thr biosynthesized by specific glycosyltransferases enzymes. Thus, mutations in specific genes that encode such enzymes lead to hypoglycosylation of alpha-dystroglycan (alpha-DG), which results in serious dystroglycanopathies, besides being involved in the development of epithelial tumors. On the other hand, tumoral mucins, whose structures are quite similar to alpha-DG glycoproteins, have abnormal and incomplete glycans, such as alphaGalNAc (Tn), Neu5Acalpha2-6betaGalNAc (STn) and betaGal1-3alphaGalNAc (TF), known as Tumor Associated Carbohydrate Antigens (TACAs), which are considered tumor markers of clinical relevance. Therefore, the synthesis of glycoconjugates mimetics of alpha-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-alpha-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) alphaMan-ThrOH 1, alphaGalNAc-ThrOH 2 and betaGal1-3alphaGalNAc-ThrOH 3, which are key precursors for obtaining alpha-DG and tumor mucins glycopeptides.