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

Autor: Stadler KA; Institute of Chemistry/Organic and Bioorganic Chemistry, University of Graz, Graz, Austria., Ortiz-Joya LJ; Institute of Chemistry/Organic and Bioorganic Chemistry, University of Graz, Graz, Austria.; Programa de Estudio y Control de Enfermedades Tropicales (PECET), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.; Department of Biochemistry, McGill University, Montreal, Canada., Singh Sahrawat A; Institute of Molecular Biosciences, University of Graz, Graz, Austria.; Innophore GmbH, Graz, Austria., Buhlheller C; Institute of Molecular Biosciences, University of Graz, Graz, Austria., Gruber K; Institute of Molecular Biosciences, University of Graz, Graz, Austria.; Innophore GmbH, Graz, Austria.; Field of Excellence BioHealth, University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria., Pavkov-Keller T; Institute of Molecular Biosciences, University of Graz, Graz, Austria.; Field of Excellence BioHealth, University of Graz, Graz, Austria.; BioTechMed-Graz, Graz, Austria., O'Hagan TB; Department of Biochemistry, McGill University, Montreal, Canada., Guarné A; Department of Biochemistry, McGill University, Montreal, Canada., Pulido S; Programa de Estudio y Control de Enfermedades Tropicales (PECET), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia.; LifeFactors ZF SAS, Rionegro, Colombia., Marín-Villa M; Programa de Estudio y Control de Enfermedades Tropicales (PECET), Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia., Zangger K; Institute of Chemistry/Organic and Bioorganic Chemistry, University of Graz, Graz, Austria. klaus.zangger@uni-graz.at.; Field of Excellence BioHealth, University of Graz, Graz, Austria. klaus.zangger@uni-graz.at.; BioTechMed-Graz, Graz, Austria. klaus.zangger@uni-graz.at., Gubensäk N; Institute of Molecular Biosciences, University of Graz, Graz, Austria. nina.gubensaek@uni-graz.at.
Jazyk: angličtina
Zdroj: Scientific reports [Sci Rep] 2024 May 02; Vol. 14 (1), pp. 10039. Date of Electronic Publication: 2024 May 02.
DOI: 10.1038/s41598-024-59654-8
Abstrakt: 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 (TcAkt) 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 TcAkt and its binding to phosphatidylinositol phosphate ligands (PIP). Experimental data combined with Alpha Fold proposes a model for the mechanism of action of TcAkt involving a PIP-induced disruption of the intramolecular interface between the kinase and the PH domain resulting in an open conformation enabling TcAkt kinase activity. Further docking experiments reveal that TcAkt is recognized by human inhibitors PIT-1 and capivasertib, and TcAkt inhibition by UBMC-4 and UBMC-6 is achieved via binding to TcAkt kinase domain. Our in-depth structural analysis of TcAkt reveals potential sites for drug development against CD, located at activity essential regions.
(© 2024. The Author(s).)
Databáze: MEDLINE
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