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Synthesis, purification and characterization of FLAG peptides and analogues for immobilization of SGLT2 or iSGLT2 inhibitors for evaluation of cardiac and renal targets

Grant number: 24/01750-8
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): May 01, 2024
Effective date (End): April 30, 2025
Field of knowledge:Biological Sciences - Biochemistry - Chemistry of Macromolecules
Principal Investigator:Eduardo Festozo Vicente
Grantee:Vitor Sampaio Fernandes
Host Institution: Faculdade de Ciências e Engenharia. Universidade Estadual Paulista (UNESP). Campus de Tupã. Tupã , SP, Brazil
Associated research grant:21/14534-3 - Pleiotropic effects of antidiabetic agents and their pharmacological targets: renoprotective mechanisms beyond glycemic control, AP.TEM

Abstract

Nowadays, the prevalence of diabetes mellitus in the world is high, where its emergence is associated with secondary complications, in addition to the role of highly industrialized foods in the diet, directly impacting global health. The main risk factors for developing diabetes are genetic predisposition, inadequate diet and deficiency in insulin production. It should be noted that, despite the medications available to control glycemic levels, many still have undesired side effects. The role of the kidneys in glucose reabsorption has been much discussed, where it is emphasized that the inhibition of sodium-glucose co-transporter 2 (SGLT2) has become a central approach for reducing glycemic levels. In this way, the effectiveness of gliflozins in the treatment of type 2 diabetes mellitus can be seen, which, in addition, has demonstrated beneficial effects in heart failure, which are not explained solely by the inhibition of SGLT2 in the proximal tubule. Within this class of drugs, empagliflozin is highlighted as a potent SGLT2 inhibitor for the treatment of type 2 diabetes mellitus. Therefore, the research aims to explore the role of peptides as possible supports for the immobilization of SGLT2 or iSGLT2 inhibitors. Thus, through the immobilization of empagliflozin linked to specific FLAG-type peptides, the possibility of this evaluation will be opened. In order to achieve the final objective, the solid phase synthesis of FLAG peptides and strategically modified analogues will be carried out as a "linker" for conjugation with structurally modified empagliflozin via "Click Chemistry". Therefore, by obtaining these conjugates, the aim is to develop chemical probes for use, via the immunoaffinity chromatography technique and mass spectrometry analyses, to evaluate new cardiac and renal targets.

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