ALLOSTERY TO DISRUPT PROTEIN-PROTEIN INTERACTIONS WITH SMALL MOLECULES.

LEROUX ALEJANDRO EZEQUIEL; SACERDOTI MARIANA; GROSS LISSY Z F; ACEBEDO MARTINEZ MACARENA; BIONDI RICARDO MIGUEL

Mendoza

Congreso; Congreso SAIB 2022; 2022

Sociedad Argentina de Investigaciones en Bioquímica y Biología Molecular

It is commonly considered that protein-protein interactions are extremely difficult to target using small molecules. Our group uses a chemical biology approach to study the allosteric, regulatory, mechanisms of protein kinases involved in growth factor signaling downstream of PI3-kinase. Over the years we have described small molecules that target a regulatory site in AGC kinases called “PIF-Pocket”, and allosterically affect the active site, ATP-binding site. We also have shown that molecules that bind to the active site of protein kinases can stimulate or inhibit protein-protein interactions at the PIF-pocket regulatory site, by a mechanism that we have termed “reverse allostery”. The reverse allosteric effects are widely produced by protein kinases inhibitors that target the ATP-binding site, although the phenomenon has been almost completely unperceived by pharmaceutical industries. The presence of a reverse allosteric effect is also the cause of the paradoxical effects on the protein kinases signal transduction detected for certain inhibitors. Thus, using the knowledge of the molecular mechanism involved in the bidirectional allostery, it becomes possible to exploit it to break protein-protein interactions between protein kinases in their protein complexes (Trends Biochem Sci 45(1):27-41, 2020). We will summarize our detailed research on the protein kinase PDK1 as a model of allosteric protein and will analyze the results in the context of the modern models of allostery, "conformational selection" and "population shift". We suggest that the principles of allostery should be used to rationalize new approaches to push forward the discovery of novel drugs that break protein-protein interactions. In line with the allosteric mechanism to disrupt protein kinase interactions, we also hypothesized that such a mechanism could also be used to break the interactions between other proteins, for example, between the angiotensin converting enzyme II (ACE2) and SARS-CoV-2 spike protein, which could be used as treatment against coronavirus infection (ChemMedChem. 15(18):1682-1690, 2020). Current studies confirm that compounds with allosteric mechanism can indeed disrupt the interaction between ACE2 and Spike.