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EFFECT OF HEPARIN ON THE INHIBITORY PROCESS OF COMPOUNDS OF THE 2-AMINOTHIAZOLE CLASS ON THE ACTIVITY OF CATEPSINS B AND L

Grant number: 23/16632-8
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): March 01, 2024
Effective date (End): February 28, 2025
Field of knowledge:Biological Sciences - Biochemistry - Enzymology
Principal Investigator:Wagner Alves de Souza Júdice
Grantee:Maria Luiza Gonçalves Gallego Rosa
Host Institution: Pró-Reitoria Acadêmica. Universidade de Mogi das Cruzes (UMC). Campus da Sede Mogi das Cruzes. Mogi das Cruzes , SP, Brazil

Abstract

Cathepsins B and L, cysteine lysosomal proteases, are significant targets in the development of a variety of therapeutic agents due to their involvement in various disease conditions. They are associated with cancer progression due to their ability to degrade the extracellular matrix, facilitating invasion, angiogenesis, and metastasis, as well as promoting viral replication in human cells. Studies suggest that Glycosaminoglycans (GAGs) play a fundamental role in cellular signaling, modulating a myriad of biochemical processes. Protein-GAG interactions may favor protection against proteolytic degradation, modulation of biological activity, and in this regard, studies have shown the activation of cysteine proteases modulated by GAGs. Additionally, they accelerate the auto-catalytic activation of cathepsins L and B and affect the activity and stability of mature cysteine cathepsins. Increased activity of cathepsins B and L has been observed in cases of breast cancer, prostate cancer, and early stages of gastric carcinoma, making them potential markers for these diseases and suggesting prognostic value for recurrences of these tumor types. Therefore, inhibitors of these peptidases should be considered in advanced stages of cancer. In this context, it becomes important to evaluate the behavior of inhibitors in an environment containing GAG to identify possible interferences with the inhibitory process, as GAGs are capable of modulating the activity of cysteine cathepsins. In addition, the literature reports that GAGs can undergo conformational changes induced by coordination compounds such as platinum, consequently modulating the biological function of GAG. A platinum complex was able to inhibit the activity of GAGs by forming non-covalent interactions, thus preventing the formation of the Growth Factor and Heparan Sulfate (HS) complex and consequently reducing metastasis by HS loss of function. Therefore, our objective will be to evaluate the effects of heparin as a model GAG on the inhibitory activity of compounds from the class of 2-aminotiazol on cysteine proteases cathepsins B and L through kinetic assays via inhibition screening. Subsequently, we will select the best compounds for determining the inhibitory potential in the absence and presence of heparin.

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