Structural investigation of Trypanosoma cruzi Akt-like kinase as drug target against Chagas disease

According to the World Health Organization, Chagas disease (CD) is the most prevalent poverty-promoting neglected tropical disease. Alarmingly, climate change is accelerating the geographical spreading of CD causative parasite, Trypanosoma cruzi , which additionally increases infection rates . Still, CD treatment remains challenging due to a lack of safe and efficient drugs. In this work, we analyze the viability of T. cruzi Akt- like kinase ( Tc Akt) as drug target against CD including primary structural and functional information about a parasitic Akt protein. Nuclear Magnetic Resonance derived information in combination with Molecular Dynamics simulations offer detailed insights into structural properties of the pleckstrin homology (PH) domain of Tc Akt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of Tc Akt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling Tc Akt kinase activity. Further docking experiments reveal that Tc Akt is recognized by human inhibitors PIT-1 and capivasertib, and Tc Akt inhibition by UBMC-4 and UBMC-6 is achieved via binding to Tc Akt kinase domain. Our in-depth structural analysis of Tc Akt reveals potential sites for drug development against CD, located at activity essential regions.