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

Grant number: 14/23280-1
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): January 01, 2015
Effective date (End): 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.

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