Peptides dimerization and cyclization studies and the effect on the inhibitory activity of DNA topoisomerases

• Grant number: 18/19468-6
• Support type: Regular Research Grants
• Duration: April 01, 2019 - January 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry - Chemistry of Macromolecules
• Principal researcher: Reinaldo Marchetto
• Grantee: Reinaldo Marchetto
• Home Institution: Instituto de Química (IQ). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil
• Assoc. researchers: Aderson Zottis ; Edson Crusca Junior

Abstract

The emergence and spread of pathogenic bacterial strains resistant to currently available antimicrobial agents represent the major public health problem in the world. In addition, studies show that by 2050 there will be a significant increase in the number of deaths caused by multiresistant bacterial species and cancer. Given the seriousness of this scenario, it becomes urgent and of great importance the research and development of new classes of antimicrobials and antitumorals that can act on different targets. In this sense, DNA topoisomerases, essential enzymes for cellular viability, have become a very attractive target for the action of different drugs, including synthetic peptides, representing a promising strategy in the development of new therapeutic agents. Prospects for the development of new drugs with antibacterial and antitumor action include the study of peptide molecules obtained by combinatorial chemistry, that is, a technique that uses the chemical combination of all amino acids, potentially in all combinations and permutations, allowing rapid production of thousands of molecules. Several studies have been conducted using combinatorial peptide libraries as tools for the discovery of novel enzyme inhibitors important for DNA metabolism, such as tyrosine recombinases and topoisomerases. These enzymes share structural and mechanistic characteristics, tyrosine-recombinases being considered a sub-branch of the topoisomerase type IB family. A series of inhibitor peptides of various catalytic tyrosine-recombinase steps has been identified from screenings of combinatorial libraries, which represent a great potential to be explored, with dimeric / or cyclic analogs of these peptides becoming strong candidates for the development of novel therapeutics inhibitors of DNA topoisomerases. The aim of this project is to evaluate the effect of dimerization on the mechanism of action and on the biological activity of identified peptides from combinatorial libraries search, as inhibitors of topoisomerases. (AU)