Pharmacological assessment defines Leishmania donovani casein kinase 1 as a drug target and reveals important functions in parasite viability and intracellular infection

Antimicrobial Agents and Chemotherapy
Najma RachidiGerald F Späth

Abstract

Protein kinase inhibitors have emerged as new drugs in various therapeutic areas, including leishmaniasis, an important parasitic disease. Members of the Leishmania casein kinase 1 (CK1) family represent promising therapeutic targets. Leishmania casein kinase 1 isoform 2 (CK1.2) has been identified as an exokinase capable of phosphorylating host proteins, thus exerting a potential immune-suppressive action on infected host cells. Moreover, its inhibition reduces promastigote growth. Despite these important properties, its requirement for intracellular infection and its chemical validation as a therapeutic target in the disease-relevant amastigote stage remain to be established. In this study, we used a multidisciplinary approach combining bioinformatics, biochemical, and pharmacological analyses with a macrophage infection assay to characterize and define Leishmania CK1.2 as a valid drug target. We show that recombinant and transgenic Leishmania CK1.2 (i) can phosphorylate CK1-specific substrates, (ii) is sensitive to temperature, and (iii) is susceptible to CK1-specific inhibitors. CK1.2 is constitutively expressed at both the promastigote insect stage and the vertebrate amastigote stage. We further demonstrated that reduction...Continue Reading

References

Mar 1, 1991·Molecular and Biochemical Parasitology·D ZilbersteinC L Jaffe
Sep 1, 1997·Nucleic Acids Research·S F AltschulD J Lipman
Jan 10, 1998·The Journal of Biological Chemistry·N Sacerdoti-Sierra, C L Jaffe
Oct 8, 1998·Molecular and Biochemical Parasitology·Y SaarD Zilberstein
Apr 6, 2000·The Journal of Biological Chemistry·N MashhoonJ Kuret
Feb 22, 2002·Journal of Medicinal Chemistry·James F CallahanNicholas J Laping
Mar 5, 2002·The Journal of Biological Chemistry·Erik J EideDavid M Virshup
Jul 16, 2002·International Journal for Parasitology·Lita L VieiraCharles L Jaffe
Oct 22, 2002·Molecular and Biochemical Parasitology·Carmenza SpadaforaSantiago Castanys
Oct 11, 2003·Molecular and Biochemical Parasitology·Sophie GoyardStephen M Beverley
Feb 13, 2004·Bioinformatics·Michele ClampGeoffrey J Barton
Mar 17, 2004·Biochimica Et Biophysica Acta·Christian Doerig
Jul 27, 2004·Antimicrobial Agents and Chemotherapy·Karen M GrantJeremy C Mottram
Feb 22, 2005·Cellular Signalling·Uwe KnippschildMartin Stöter
Apr 7, 2005·Molecular and Biochemical Parasitology·Robert G K DonaldPaul A Liberator
Apr 7, 2005·Molecular and Biochemical Parasitology·Efrat BarakDan Zilberstein
Oct 13, 2005·The FEBS Journal·Stephen F AltschulYi-Kuo Yu
Nov 1, 2005·Lancet·Henry W MurrayNancy G Saravia
Aug 8, 2006·International Journal for Parasitology·John J AlloccoBakela Nare
Apr 17, 2007·Protein Expression and Purification·Jens ReinhardtLaurent Meijer
May 8, 2007·International Journal for Parasitology·Miguel A MoralesGerald F Späth
Sep 12, 2007·Bioinformatics·M A LarkinD G Higgins
Sep 14, 2007·The Biochemical Journal·Jenny BainPhilip Cohen
Jan 19, 2008·Proteomics·Miguel A MoralesGerald F Späth
Feb 20, 2008·Genome Biology·J Maxwell SilvermanNeil E Reiner
Jun 25, 2008·Journal of Microbiological Methods·Orly Shimony, Charles L Jaffe
Dec 31, 2008·Journal of Cellular Biochemistry·Mauricio BudiniJorge E Allende
Jan 20, 2009·Bioinformatics·Andrew M WaterhouseGeoffrey J Barton
May 20, 2009·Molecular and Biochemical Parasitology·Michael D Urbaniak
Aug 4, 2009·Bioinformatics·Carsten Kemena, Cedric Notredame
Sep 18, 2009·The Journal of Biological Chemistry·Anne-Sophie HuartTed R Hupp
Nov 11, 2009·Molecular and Biochemical Parasitology·Daniel PaapeToni Aebischer
Apr 21, 2010·Proceedings of the National Academy of Sciences of the United States of America·Miguel A MoralesGerald F Späth
May 11, 2010·PLoS Neglected Tropical Diseases·Jair L Siqueira-NetoLucio H Freitas-Junior
Oct 1, 2010·The Journal of Immunology : Official Journal of the American Association of Immunologists·Judith Maxwell SilvermanNeil E Reiner
Jan 25, 2011·Pharmacology & Therapeutics·Richard Eglen, Terry Reisine
Jul 13, 2011·Nature Reviews. Microbiology·Paul Kaye, Phillip Scott
Dec 25, 2012·Antimicrobial Agents and Chemotherapy·Aude L FoucherGerald F Späth

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Citations

Aug 12, 2014·Microbes and Infection·Peter E Kima
Nov 14, 2015·Expert Opinion on Therapeutic Targets·Giorgio Cozza, Lorenzo A Pinna
Sep 19, 2015·European Journal of Medicinal Chemistry·Pascal MarchandPatrice Le Pape
Mar 25, 2015·Cellular Microbiology·Gerald F SpäthNajma Rachidi
May 16, 2014·The Biochemical Journal·Andrea VenerandoLorenzo A Pinna
Jan 16, 2018·BioMed Research International·Daniel MartelNajma Rachidi
May 17, 2019·Bioscience, Biotechnology, and Biochemistry·Thomas BöhmJoachim Bischof
Sep 2, 2019·Parasitology Research·Sarah HendrickxL Maes
Jun 9, 2017·PLoS Neglected Tropical Diseases·Suzanne LamotteEric Prina
Nov 23, 2019·Journal of Enzyme Inhibition and Medicinal Chemistry·Paula Martínez de IturrateCarmen Gil
Oct 1, 2020·Scientific Reports·Constanze Kröber-BoncardoJoachim Clos
Dec 29, 2020·Computational and Structural Biotechnology Journal·Janne Grünebast, Joachim Clos
Nov 4, 2020·Infection and Immunity·Pragya Prasanna, Arun Upadhyay
Apr 20, 2021·Frontiers in Cellular and Infection Microbiology·Najma RachidiGerald F Späth
May 15, 2021·Frontiers in Chemistry·Crhisllane Rafaele Dos Santos Vasconcelos, Antonio Mauro Rezende
Feb 1, 2018·ACS Infectious Diseases·Nathaniel G JonesJeremy C Mottram

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