Development of mucin glycoconjugates with diagnostic and therapeutic applications in muscular dystrophies and cancer

Abstract

Hypoglycosylated ±-dystroglycan (±-DG) mucins are directly involved in pathological processes such as dystroglycanopathies (Congenital Muscular Distrophies - CMD) and epithelial tumors, while Tumor Associated Carbohydrate Antigens (TACAs)-containing glycopeptides, present in mucins of malignantly transformed cells, are super expressed in various tumor types, being considered potential targets for the development of synthetic antitumor vaccines. Currently, there is no available therapy for treatment of CMDs and the diagnostics for these dystroglycanopathies is based, mainly, on clinical manifestations associated with limited immunohistochemical methods. Regarding treatment and diagnostics of tumors, in Brazil, researches directed to the development of synthetic antitumor vaccines and monoclonal antibodies are still incipient and lagged if compared to other developed countries.Therefore, this project has as fundamental objective the insertion of a new transdisciplinary research line in Glycobiology at the Faculty of Pharmaceutical Sciences of Ribeirão Preto (FCFRP-USP) directed to the chemical synthesis of glycoconjugates mimetics of ±-DG and tumor (TACAs) mucins as tools for development of new diagnostic and therapeutic strategies against muscular dystrophies and cancer. The consolidation of this proposal must be achieved by using different in solution and solid phase synthesis methods of glycopeptides, associated to biological assays involving the assembly of anti-±-DG and anti-TACAs antibodies by Phage Display, and their linkage to radioisotopes; and immunization assays of murine models and flow cytometry for evaluation of TACAs glycopeptide as potential antitumor vaccine. (AU)