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| Author(s): |
Marcelo Fiori Marchiori
Total Authors: 1
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| Document type: | Master's Dissertation |
| Press: | Ribeirão Preto. |
| Institution: | Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) |
| Defense date: | 2018-08-16 |
| Examining board members: |
Vanessa Leiria Campo;
Daniel Fabio Kawano;
Mirela Ines de Sairre
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| Advisor: | Ivone Carvalho; Vanessa Leiria Campo |
| Abstract | |
Mucins are high molecular weight glycoproteins that keep as fundamental characteristic the linkage between ?GalNAc sugar and amino acid residues of Ser/Thr (?GalNAc-Ser/Thr). In tumors, mucin production is dysregulated once their biosynthetic mechanisms are impaired with consequent alteration in the O-glycosylation patterns. As a result, abnormal and incomplete glycans are formed, which are continuously expressed in tumor cells and generally absent in healthy tissues. The continual exposure of these glycans gives them the name of Tumor Associated Carbohydrates Antigens (\"TACAs\"), such as Tn (?GalNAc-Ser/Thr), sialyl-Tn (Neu5Ac???6-?GalNAc-Ser/Thr) and TF (?Gal1-3?GalNAc-Ser/Thr) antigens. Among tumor mucins, MUC1 is the most extensively investigated and is composed by tandem repeat regions HGVTSAPDRPAPGSTAPPA sequence with five potential sites for O-glycosylation (O-?GalNAc). In view of the importance of \"TACAS\" as tumor markers of clinical significance, they started to be used in clinical trials as therapeutic vaccines, but with limited success due to their low immunogenicity. Thus, considering their constant presence in tumor mucins such as MUC1, synthetic glycopeptides that not only mimic the peptide sequence of the MUC1 type (PDTRP), but also possess TACAS analogs linked to their peptide chain have high potential for application in the development of anti-tumor vaccines. Thus, the aim of this study was the synthesis of glycocopeptide Neu5Ac?2-triazole-6-?GalNAc-Thr-Arg-Pro-Ala-Pro-GlyOH 19B ???, mimicking mucin MUC1 type tumors and owing STn analogue. In order to obtain glycopeptide 19B ????it was firstly necessary to synthesize the triazole glycoamino acid Neu5Ac-?/?2-triazol-6-?GalNAc-ThrOH 20B ????by sequential reactions of CuAAc (\'click chemistry\') between the building blocks 68 and 24 ??? and hydrogenolysis. The azide precursor N3-6-?GalNAc-ThrOBn 68 was obtained by two different synthetic routes, as well as the intermediate alkyne. The use of 20B ?/? in coupling reactions with amino acid (SPPS) provided the glycopeptide 19B ?/? after HPLC purification. The synthesis and purifications of the glycopeptide model NHAcPro-Asp-[?GalNAc]Thr-Arg-Pro-GlyOH 21, which owns the natural Tn antigen was also performed. Future steps of conjugation of 19B ????e 21 to carrier protein BSA and immunization assays with mice (BALB/c) will be made to evaluate the ability of these glycopeptides to induce immune response. (AU) | |
| FAPESP's process: | 16/04699-7 - Synthesis of mucin glycopeptide containing tumor antigen analogue with potential therapeutic applications in cancer |
| Grantee: | Marcelo Fiori Marchiori |
| Support Opportunities: | Scholarships in Brazil - Master |