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

Green, Judith L and Moon, Robert and Whalley, David and Bowyer, Paul W and Wallace, Claire and Rochani, Ankit and Nageshan, Rishi K and Howell, Steven A and Grainger, Munira and Jones, Hayley M and Ansell, Keith H and Chapman, Timothy M and Taylor, Debra L and Osborne, Simon A and Baker, David A and Tatu, Utpal and Holder, Anthony A (2016) 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. In: ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 60 (3). pp. 1464-1475.

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Abstract

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.

Item Type:	Journal Article
Publication:	ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Publisher:	AMER SOC MICROBIOLOGY
Additional Information:	Copy right for this article belongs to the AMER SOC MICROBIOLOGY, 1752 N ST NW, WASHINGTON, DC 20036-2904 USA
Department/Centre:	Division of Biological Sciences > Biochemistry
Date Deposited:	22 Jun 2016 06:20
Last Modified:	22 Jun 2016 06:20
URI:	http://eprints.iisc.ac.in/id/eprint/54057

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