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

ACEBEDO MARTINEZ, M; SACERDOTI, M; GROSS, LZF; DI LELLA, S; GIRONACCI, M; BIONDI, RM; LEROUX, AE

Buenos Aires

Conferencia; Frontiers in Biosciences 4; 2023

IBioBA

Allostery refers to the process in which an interaction at one specific siteon a protein, known as the allosteric site, causes a conformational change thatimpacts the function of a distant site, e.g the active site. It should be notedthat allostery is bidirectional, meaning that binding at the active site canalso induce a conformational change at the regulatory site, based on thethermodynamic relationship between different conformations. In our research, wehave adopted a chemical biology approach to investigate the regulatorymechanisms of protein kinases involved in growth factor signaling downstream ofPI3-kinase. Specifically, we have identified small molecules that target aregulatory site called the "PIF-Pocket" within the AGC family ofprotein kinases. These molecules exert an allosteric influence on the activesite, ATP binding site. Additionally, we have demonstrated that compoundsbinding to the active site of protein kinases can either stimulate or inhibitprotein-protein interactions at the regulatory site of the PIF-Pocket. We havetermed this phenomenon "reverse allostery" (Trends Biochem Sci45(1):27-41, 2020). Building upon the concept of allosteric disruption ofprotein kinase interactions, we have also proposed that a similar mechanismcould be utilized to disrupt interactions between other proteins, such as theangiotensin-converting enzyme II (ACE2) and the SARS-CoV-2 spike protein. Thisapproach could potentially serve as a preventive treatment against coronavirusinfection (ChemMedChem. 15(18):1682-1690, 2020). We will present our ongoingstudies on the allosteric modulation of protein-protein interactions in thefields of protein kinases and ACE2.