Allostery to disrupt protein-protein interactions with small molecules

LEROUX, AE; SACERDOTI, M; GROSS, LZF; ACEBEDO, M; BIONDI, RM

Mendoza

Congreso; LVIII Reunión Científica anual; 2022

Sociedad Argentina de Investigación en Bioquímica y Biología Molecular

It is commonly considered that protein-proteininteractions are extremely difficult to target using small molecules. Our groupuses a chemical biology approach to study the allosteric, regulatory,mechanisms of protein kinases involved in growth factor signaling downstream ofPI3-kinase. Over the years we have described small molecules that target aregulatory site in AGC kinases called “PIF-Pocket”, and allosterically affectthe active site, ATP-binding site. We also have shown that molecules that bindto the active site of protein kinases can stimulate or inhibit protein-proteininteractions at the PIF-pocket regulatory site, by a mechanism that we havetermed “reverse allostery”. The reverse allosteric effects are widely producedby protein kinases inhibitors that target the ATP-binding site, although thephenomenon has been almost completely unperceived by pharmaceutical industries.The presence of a reverse allosteric effect is also the cause of theparadoxical effects on the protein kinases signal transduction detected forcertain inhibitors. Thus, using the knowledge of the molecular mechanisminvolved in the bidirectional allostery, it becomes possible to exploit it tobreak protein-protein interactions between protein kinases in their proteincomplexes (Trends Biochem Sci 45(1):27-41, 2020).  We will summarize our detailed research onthe protein kinase PDK1 as a model of allosteric protein and will analyze theresults in the context of the modern models of allostery, "conformationalselection" and "population shift". We suggest that theprinciples of allostery should be used to rationalize new approaches to pushforward 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 interactionsbetween other proteins, for example, between the angiotensin converting enzymeII (ACE2) and SARS-CoV-2 spike protein, which could be used as treatmentagainst coronavirus infection (ChemMedChem. 15(18):1682-1690, 2020). Currentstudies confirm that compounds with allosteric mechanism can indeed disrupt theinteraction between ACE2 and Spike.