title: Ketanserin, an antidepressant, exerts its antileishmanial action via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme of Leishmania donovani.
abstract: Leishmaniasis is one of the major health problems existing globally. The current chemotherapy for leishmaniasis presents several drawbacks like toxicity and increased resistance to existing drugs, and hence, there is a necessity to look out for the novel drug targets and new chemical entities. Current trend in drug discovery arena is the "repurposing" of old drugs for the treatment of diseases. In the present study, an antidepressant, ketanserin, was found lethal to both Leishmania donovani promastigotes and intracellular amastigotes with no apparent toxicity to the cells. Ketanserin killed promastigotes and amastigotes with an IC50 value of 37 μM and 28 μM respectively, in a dose-dependent manner. Ketanserin was found to inhibit L. donovani recombinant 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) enzyme with an IC50 value of 43 μM. Ketanserin treated promastigotes were exogenously supplemented with sterols like ergosterol and cholesterol to rescue cell death. Ergosterol could recover the inhibition partially, whereas cholesterol supplementation completely failed to rescue the inhibited parasites. Further, HMGR-overexpressing parasites were generated by transfecting Leishmania promastigotes with an episomal pspα hygroα-HMGR construct. Wild-type and HMGR overexpressors of L. donovani were used to study the effect and mode of action of this inhibitor. The HMGR overexpressors showed twofold resistance to ketanserin. These observations suggest that the lethal effect of ketanserin is due to inhibition of HMGR, the rate-limiting enzyme of the ergosterol biosynthetic pathway. Since targeting of the sterol biosynthetic pathway enzymes may be useful therapeutically, the present study may have implications in treatment of leishmaniasis.
authors.affiliation: Department of Biotechnology, National Institute of Pharmaceutical Education and Research, SAS Nagar, Mohali, Punjab, 160062, India, sushmasingh76@rediffmail.com.
authors.forename: Sushma
authors.initials: S
authors.lastname: Singh
authors.forename: Neeradi
authors.initials: N
authors.lastname: Dinesh
authors.forename: Preet Kamal
authors.initials: PK
authors.lastname: Kaur
authors.forename: Baigadda
authors.initials: B
authors.lastname: Shamiulla
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D003067:Coenzymes / Q000494:pharmacology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007650:Ketanserin / Q000494:pharmacology*; D007893:Leishmania donovani / Q000187:drug effects*
chemical_list: D000928:Antidepressive Agents; D003067:Coenzymes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007650:Ketanserin; D006903:Hydroxymethylglutaryl CoA Reductases
references.citation: Eur J Pharmacol. 2013 Dec 5;721(1-3):126-32
references.pmid: 24076184
references.citation: J Biol Chem. 2001 Apr 13;276(15):11674-82
references.pmid: 11148203
references.citation: Appl Microbiol Biotechnol. 2010 Jan;85(4):869-83
references.pmid: 19820926
references.citation: Am J Ther. 2009 Mar-Apr;16(2):178-82
references.pmid: 19300044
references.citation: Indian J Med Res. 2006 Mar;123(3):399-410
references.pmid: 16778319
references.citation: Eur J Clin Pharmacol. 1990;39(3):217-20
references.pmid: 2257855
references.citation: Int J Antimicrob Agents. 2009 Feb;33(2):185-6
references.pmid: 18996682
references.citation: Antimicrob Agents Chemother. 2014;58(3):1596-602
references.pmid: 24366748
references.citation: Exp Biol Med (Maywood). 2004 Sep;229(8):781-6
references.pmid: 15337832
references.citation: PLoS Negl Trop Dis. 2012;6(12):e1987
references.pmid: 23301108
references.citation: Trop Med Int Health. 2001 Nov;6(11):849-54
references.pmid: 11703838
references.citation: Interdiscip Perspect Infect Dis. 2009;2009:642502
references.pmid: 19680554
references.citation: J Med Chem. 2008 Feb 28;51(4):897-908
references.pmid: 18220332
references.citation: Toxicol Sci. 2012 Feb;125(2):569-77
references.pmid: 22048642
references.citation: Parasitol Res. 2013 May;112(5):2095-9
references.pmid: 23392902
references.citation: Angew Parasitol. 1990 Nov;31(4):231-7
references.pmid: 2085212
references.citation: Am J Trop Med Hyg. 2009 Apr;80(4):580-2
references.pmid: 19346379
references.citation: FEBS Lett. 2002 Jan 16;510(3):141-4
references.pmid: 11801242
references.citation: PLoS One. 2013;8(1):e55497
references.pmid: 23383204
references.citation: Curr Opin Infect Dis. 2003 Oct;16(5):397-401
references.pmid: 14501991
references.citation: Pharmacol Ther. 2010 Jul;127(1):19-40
references.pmid: 20420853
references.citation: FEMS Microbiol Lett. 2006 Sep;262(1):9-13
references.pmid: 16907733
references.citation: Int Immunopharmacol. 2004 Feb;4(2):185-92
references.pmid: 14996410
references.citation: J Immunol Methods. 1983 Dec 16;65(1-2):55-63
references.pmid: 6606682
references.citation: Hypertension. 1986 Feb;8(2):167-73
references.pmid: 2935497
references.citation: Biochem J. 2000 Jul 1;349(Pt 1):27-34
references.pmid: 10861207
references.citation: Parasitol Res. 2007 Jul;101(2):317-24
references.pmid: 17294216
references.citation: Hypertension. 1984 Jan-Feb;6(1):100-9
references.pmid: 6319278
references.citation: Cardiovasc Drugs Ther. 1990 Jan;4 Suppl 1:69-72
references.pmid: 1981023
references.citation: EMBO J. 1992 Oct;11(10):3601-8
references.pmid: 1396560
references.citation: Naunyn Schmiedebergs Arch Pharmacol. 1990 Oct;342(4):477-82
references.pmid: 2123968
references.citation: Eur J Clin Chem Clin Biochem. 1992 Feb;30(2):55-61
references.pmid: 1581411
references.citation: Science. 1984 Nov 23;226(4677):977-9
references.pmid: 6505677
references.citation: Microb Pathog. 2014 Jan;66:14-23
references.pmid: 24239940
references.citation: J Antimicrob Chemother. 2008 May;61(5):1120-4
references.pmid: 18272513
references.citation: Biophys J. 2006 Mar 1;90(5):1639-49
references.pmid: 16326903
references.citation: Lancet. 2005 Oct 29-Nov 4;366(9496):1561-77
references.pmid: 16257344
references.citation: J Vis Exp. 2012 Dec 30;(70):
references.pmid: 23299097
references.citation: Biochem J. 1992 Aug 15;286 ( Pt 1):9-11
references.pmid: 1355650
references.citation: J Med Chem. 2009 Apr 23;52(8):2603-12
references.pmid: 19317451
references.citation: Malar J. 2010 May 25;9:139
references.pmid: 20497586
references.citation: Biochem Pharmacol. 1990 Mar 1;39(5):935-40
references.pmid: 1968745