DEVELOPMENT OF ALLOSTERIC MODULATORS TO REGULATE ENZYMATIC ACTIVITY AND PROTEIN-PROTEIN INTERACTIONS

ACEBEDO MARTINEZ MACARENA; SACERDOTI MARIANA; GROSS LISSY Z F; DI LELLA SANTIAGO; GIRONACCI MARIELA; BIONDI RICARDO MIGUEL; LEROUX ALEJANDRO EZEQUIEL

Ciudad Autónoma de Buenos Aires

Congreso; Frontiers in Bioscience; 2023

Instituto de Investigación en Biomedicina de Buenos Aires - Partner Max Planck Society

Allostery refers to the process in which an interaction at one specific site on a protein, known as the allosteric site, causes a conformational change that impacts the function of a distant site, e.g the active site. It should be noted that allostery is bidirectional, meaning that binding at the active site can also induce a conformational change at the regulatory site, based on the thermodynamic relationship between different conformations. In our research, we have adopted a chemical biology approach to investigate the regulatory mechanisms of protein kinases involved in growth factor signaling downstream of PI3-kinase. Specifically, we have identified small molecules that target a regulatory site called the "PIF-Pocket" within the AGC family of protein kinases. These molecules exert an allosteric influence on the active site, ATP binding site. Additionally, we have demonstrated that compounds binding to the active site of protein kinases can either stimulate or inhibit protein-protein interactions at the regulatory site of the PIF-Pocket. We have termed this phenomenon "reverse allostery" (Trends Biochem Sci 45(1):27-41, 2020). Building upon the concept of allosteric disruption of protein kinase interactions, we have also proposed that a similar mechanism could be utilized to disrupt interactions between other proteins, such as the angiotensin-converting enzyme II (ACE2) and the SARS-CoV-2 spike protein. This approach could potentially serve as a preventive treatment against coronavirus infection (ChemMedChem. 15(18):1682-1690, 2020). We will present our ongoing studies on the allosteric modulation of protein-protein interactions in the fields of protein kinases and ACE2.