title: Antiplasmodial activity and mechanism of action of RSM-932A, a promising synergistic inhibitor of Plasmodium falciparum choline kinase.
abstract: We have investigated the mechanism of action of inhibition of the choline kinase of P. falciparum (p.f.-ChoK) by two inhibitors of the human ChoKα, MN58b and RSM-932A, which have previously been shown to be potent antitumoral agents. The efficacy of these inhibitors against p.f.-ChoK is investigated using enzymatic and in vitro assays. While MN58b may enter the choline/phosphocholine binding site, RSM-932A appears to have an altogether novel mechanism of inhibition and is synergistic with respect to both choline and ATP. A model of inhibition for RSM-932A in which this inhibitor traps p.f.-ChoK in a phosphorylated intermediate state blocking phosphate transfer to choline is presented. Importantly, MN58b and RSM-932A have in vitro inhibitory activity in the low nanomolar range and are equally effective against chloroquine-sensitive and chloroquine-resistant strains. RSM-932A and MN58b significantly reduced parasitemia and induced the accumulation of trophozoites and schizonts, blocking intraerythrocytic development and interfering with parasite egress or invasion, suggesting a delay of the parasite maturation stage. The present data provide two new potent structures for the development of antimalarial compounds and validate p.f.-ChoK as an accessible drug target against the parasite.
authors.affiliation: Division of Translational Oncology, Health Research Institute and University Hospital Fundación Jiménez-Díaz, Madrid, Spain.
authors.forename: Tahl
authors.initials: T
authors.lastname: Zimmerman
authors.forename: Carlos
authors.initials: C
authors.lastname: Moneriz
authors.forename: Amalia
authors.initials: A
authors.lastname: Diez
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Bautista
authors.forename: Teresa
authors.initials: T
authors.lastname: Gómez Del Pulgar
authors.forename: Arancha
authors.initials: A
authors.lastname: Cebrián
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Lacal
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000814:Aniline Compounds / Q000494:pharmacology*; D000962:Antimalarials / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002073:Butanes / Q000494:pharmacology*; D002738:Chloroquine / Q000494:pharmacology; D002794:Choline / Q000737:chemistry / Q000378:metabolism; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D004926:Escherichia coli / Q000235:genetics; D006801:Humans; D007700:Kinetics; D021261:Parasitic Sensitivity Tests; D010766:Phosphorylation / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011806:Quinolinium Compounds / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D053058:Trophozoites / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
chemical_list: C507944:1,4-(4-4'-Bis-((4-(dimethylamine)pyridinium-1-yl) methyl)diphenyl)butane dibromide; D000814:Aniline Compounds; D000962:Antimalarials; D000970:Antineoplastic Agents; D002073:Butanes; D004791:Enzyme Inhibitors; D015800:Protozoan Proteins; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; C000593610:RSM-932A; D011994:Recombinant Proteins; D002738:Chloroquine; D000255:Adenosine Triphosphate; D002797:Choline Kinase; D002794:Choline
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3815-21
references.pmid: 19564359
references.citation: Mol Cell. 2000 Oct;6(4):861-71
references.pmid: 11090624
references.citation: Cancer Res. 2005 Jul 1;65(13):5647-53
references.pmid: 15994937
references.citation: Nat Protoc. 2009;4(12):1899-915
references.pmid: 20010926
references.citation: Biochim Biophys Acta. 2006 Jul;1760(7):1027-38
references.pmid: 16626864
references.citation: J Med Chem. 2004 Oct 21;47(22):5433-40
references.pmid: 15481981
references.citation: J Biol Chem. 1969 Nov 10;244(21):5808-19
references.pmid: 5350937
references.citation: Biochim Biophys Acta. 2013 Jun;1834(6):1107-16
references.pmid: 23416529
references.citation: Oncogene. 2003 Dec 4;22(55):8803-12
references.pmid: 14654777
references.citation: Biochem J. 2009 Dec 14;425(1):149-58
references.pmid: 19845508
references.citation: Lancet Oncol. 2007 Oct;8(10):889-97
references.pmid: 17851129
references.citation: Antimicrob Agents Chemother. 2007 Feb;51(2):696-706
references.pmid: 17145794
references.citation: J Mol Biol. 2006 Nov 24;364(2):136-51
references.pmid: 17007874
references.citation: Assay Drug Dev Technol. 2003 Aug;1(4):527-35
references.pmid: 15090249
references.citation: Adv Enzymol Relat Areas Mol Biol. 1977;45:273-387
references.pmid: 21524
references.citation: J Biol Chem. 2010 May 21;285(21):16330-40
references.pmid: 20299452
references.citation: Cancer Res. 2004 Sep 15;64(18):6732-9
references.pmid: 15374991
references.citation: Biochem Biophys Res Commun. 2002 Aug 23;296(3):580-3
references.pmid: 12176020
references.citation: J Biol Chem. 1973 Apr 10;248(7):2364-71
references.pmid: 4572730
references.citation: PLoS One. 2010 Aug 25;5(8):e12408
references.pmid: 20811640
references.citation: Int J Oncol. 2005 Apr;26(4):999-1008
references.pmid: 15753995
references.citation: Curr Protoc Mol Biol. 2011 Apr;Chapter 10:Unit10.28
references.pmid: 21472694
references.citation: Med Res Rev. 1994 Sep;14(5):505-31
references.pmid: 7815851
references.citation: J Med Chem. 2005 May 5;48(9):3354-63
references.pmid: 15857141
references.citation: Curr Drug Deliv. 2010 Oct;7(4):312-23
references.pmid: 20695842
references.citation: Mol Biochem Parasitol. 2011 Jan;175(1):21-9
references.pmid: 20813141
references.citation: Oncogene. 2004 Oct 28;23(50):8247-59
references.pmid: 15378008
references.citation: N Engl J Med. 2009 Jul 30;361(5):455-67
references.pmid: 19641202
references.citation: Antimicrob Agents Chemother. 1986 May;29(5):814-20
references.pmid: 3524430
references.citation: IDrugs. 2001 Apr;4(4):419-26
references.pmid: 16015482
references.citation: Malar J. 2009 Dec 04;8:279
references.pmid: 19961586
references.citation: Cancer Res. 1999 Jul 1;59(13):3112-8
references.pmid: 10397253
references.citation: Malar J. 2008 Apr 21;7:62
references.pmid: 18426594
references.citation: J Biol Chem. 1953 May;202(1):431-44
references.pmid: 13061469