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:	Green JL; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom judith.green@crick.ac.uk tony.holder@crick.ac.uk., Moon RW; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom., Whalley D; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Bowyer PW; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Wallace C; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Rochani A; Department of Biochemistry, Indian Institute of Science, Bangalore, India., Nageshan RK; Department of Biochemistry, Indian Institute of Science, Bangalore, India., Howell SA; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom., Grainger M; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom., Jones HM; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Ansell KH; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Chapman TM; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Taylor DL; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Osborne SA; Centre for Therapeutics Discovery, MRC Technology, London, United Kingdom., Baker DA; Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom., Tatu U; Department of Biochemistry, Indian Institute of Science, Bangalore, India., Holder AA; The Francis Crick Institute, Mill Hill Laboratory, London, United Kingdom judith.green@crick.ac.uk tony.holder@crick.ac.uk.
Jazyk:	angličtina
Zdroj:	Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2015 Dec 28; Vol. 60 (3), pp. 1464-75. Date of Electronic Publication: 2015 Dec 28.
DOI:	10.1128/AAC.01748-15
Abstrakt:	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. (Copyright © 2016 Green et al.)
Databáze:	MEDLINE
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