DESIGN AND OBTAINING OF A NEW ALKYNE FUNCTIONALIZED FLAG PEPTIDES FOR FURTHER EVALUATION OF CARDIAC AND RENAL TARGETS

According to the International Diabetes Federation (IDF), approximately 537 million adults between the ages of 20 and 79 were affected by diabetes in 2021. By 2030, it is predicted that this number would rise to 643 million. Features such as genetic predisposition, poor diet, insulin resistance, obesity, and inactivity are the key risk factors for developing diabetes. Diabetes is often associated with increased mortality due to secondary diseases such as cardiovascular diseases and blood vessel complications. In the context, at the molecular level, kidneys play a fundamental role in glucose homeostasis, involving processes such as gluconeogenesis and glucose reabsorption through glomerular filtration, mediated by sodium/glucose transporter enzymes (SGLT). These enzymes, which are membrane proteins, fa-cilitate the transport of solutes into the cell, such as glucose, and this reabsorption occurs in the proxi-mal tubule, which is divided into three segments: S1, S2, and S3. Specific substances that act as inhibitors of SGLT1 and SGLT2, known as gliflozins (canagliflozin, dapagliflozin, and empagliflozin), have been discovered. In this way, the present study focuses on SGLT2 inhibitors, which are responsible for 90% of glucose reabsorption filtered by the kidneys. These inhibitors, initially used in the treat-ment of type 2 diabetes, have also shown benefits in patients with heart failure, reducing deaths from cardiovascular incidents and the hospitalization rate. The described study aims to synthesize different primary sequences of FLAG-type peptides with variable chain lengths, which act as probes for the binding and projection of larger molecular markers, essential for binding to specific targets, such as SGLT2 inhibitors. These peptides will be synthesized with the addition of a non-conventional synthetic amino acid, Fmoc-L-propargylglycine (Fmoc-Pra-OH), which has an alkyne group that will allow covalent binding, via Click Chemistry, between these peptides and a further modified empagliflozin with an azide functional group. The results showed that the stages of synthesis, purification, and characterization of the peptides were successful. Purification by HPLC and characterization by mass spectrometry confirmed the expected molecules, allowing the continuation of the next stages of the research.

This work was supported by FAPESP funding (Proc. Number 2021/06706-9 and undergraduate scholarship 2024/01750-8).