Imidazopyridazine Inhibitors of Plasmodium falciparum Calcium-Dependent Protein Kinase 1 Also Target Cyclic GMP-Dependent Protein Kinase and Heat Shock Protein 90 To Kill the Parasite at Different Stages of Intracellular Development
| Autor: | Timothy M. Chapman, David Whalley, Steven Howell, Simon A. Osborne, Hayley M. Jones, Claire Wallace, Munira Grainger, Rishi Kumar Nageshan, Debra L. Taylor, Keith H. Ansell, Ankit K. Rochani, Judith L. Green, Utpal Tatu, David A. Baker, Paul W. Bowyer, Robert W. Moon, Anthony A. Holder |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Plasmodium falciparum Protozoan Proteins Biochemistry Cell Line Schizogony 03 medical and health sciences Antimalarials Cyclic GMP-Dependent Protein Kinases Humans Pharmacology (medical) Experimental Therapeutics HSP90 Heat-Shock Proteins Molecular Targeted Therapy Binding site Protein kinase A Protein Kinase Inhibitors Pharmacology chemistry.chemical_classification biology Kinase Imidazoles biology.organism_classification Hsp90 3. Good health Cell biology Molecular Docking Simulation Pyridazines 030104 developmental biology Infectious Diseases Enzyme chemistry biology.protein Protein Kinases |
| Zdroj: | Antimicrobial Agents and Chemotherapy |
| ISSN: | 1098-6596 0066-4804 |
| Popis: | Imidazopyridazine compounds are potent, ATP-competitive inhibitors of calcium-dependent protein kinase 1 (CDPK1) and of Plasmodium falciparum parasite growth in vitro . Here, we show that these compounds can be divided into two classes depending on the nature of the aromatic linker between the core and the R2 substituent group. Class 1 compounds have a pyrimidine linker and inhibit parasite growth at late schizogony, whereas class 2 compounds have a nonpyrimidine linker and inhibit growth in the trophozoite stage, indicating different modes of action for the two classes. The compounds also inhibited cyclic GMP (cGMP)-dependent protein kinase (PKG), and their potency against this enzyme was greatly reduced by substitution of the enzyme's gatekeeper residue at the ATP binding site. The effectiveness of the class 1 compounds against a parasite line expressing the modified PKG was also substantially reduced, suggesting that these compounds kill the parasite primarily through inhibition of PKG rather than CDPK1. HSP90 was identified as a binding partner of class 2 compounds, and a representative compound bound to the ATP binding site in the N-terminal domain of HSP90. Reducing the size of the gatekeeper residue of CDPK1 enabled inhibition of the enzyme by bumped kinase inhibitors; however, a parasite line expressing the modified enzyme showed no change in sensitivity to these compounds. Taken together, these findings suggest that CDPK1 may not be a suitable target for further inhibitor development and that the primary mechanism through which the imidazopyridazines kill parasites is by inhibition of PKG or HSP90. |
| Databáze: | OpenAIRE |
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