title: A nonazole CYP51 inhibitor cures Chagas' disease in a mouse model of acute infection.
abstract: Chagas' disease, the leading cause of heart failure in Latin America, is caused by the kinetoplastid protozoan Trypanosoma cruzi. The sterols of T. cruzi resemble those of fungi, both in composition and in biosynthesis. Azole inhibitors of sterol 14alpha-demethylase (CYP51) successfully treat fungal infections in humans, and efforts to adapt the success of antifungal azoles posaconazole and ravuconazole as second-use agents for Chagas' disease are under way. However, to address concerns about the use of azoles for Chagas' disease, including drug resistance and cost, the rational design of nonazole CYP51 inhibitors can provide promising alternative drug chemotypes. We report the curative effect of the nonazole CYP51 inhibitor LP10 in an acute mouse model of T. cruzi infection. Mice treated with an oral dose of 40 mg LP10/kg of body weight twice a day (BID) for 30 days, initiated 24 h postinfection, showed no signs of acute disease and had histologically normal tissues after 6 months. A very stringent test of cure showed that 4/5 mice had negative PCR results for T. cruzi, and parasites were amplified by hemoculture in only two treated mice. These results compare favorably with those reported for posaconazole. Electron microscopy and gas chromatography-mass spectrometry (GC-MS) analysis of sterol composition confirmed that treatment with LP10 blocked the 14alpha-demethylation step and induced breakdown of parasite cell membranes, culminating in severe ultrastructural and morphological alterations and death of the clinically relevant amastigote stage of the parasite.
authors.affiliation: Sandler Center for Basic Research in Parasitic Diseases, University of California, San Francisco, CA 54158, USA.
authors.forename: Patricia S
authors.initials: PS
authors.lastname: Doyle
authors.forename: Chiung-Kuang
authors.initials: CK
authors.lastname: Chen
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Johnston
authors.forename: Stephanie D
authors.initials: SD
authors.lastname: Hopkins
authors.forename: Siegfried S F
authors.initials: SS
authors.lastname: Leung
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Jacobson
authors.forename: Juan C
authors.initials: JC
authors.lastname: Engel
authors.forename: James H
authors.initials: JH
authors.lastname: McKerrow
authors.forename: Larissa M
authors.initials: LM
authors.lastname: Podust
mesh_terms: D000631:Aminopyridines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000981:Antiprotozoal Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D020134:Catalytic Domain; D014355:Chagas Disease / Q000188:drug therapy* / Q000469:parasitology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007211:Indoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008809:Mice, Inbred C3H; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry; D013261:Sterols / Q000096:biosynthesis; D014349:Trypanosoma cruzi / Q000187:drug effects* / Q000201:enzymology* / Q000648:ultrastructure
chemical_list: D000631:Aminopyridines; D000981:Antiprotozoal Agents; C509352:CYP51 protein, Trypanosoma cruzi; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007211:Indoles; D015800:Protozoan Proteins; D011994:Recombinant Proteins; D013261:Sterols; C552044:alpha-((4-methylcyclohexyl)carbonylamino)-N-4-pyridinyl-1H-indole-3-propanamide; D003577:Cytochrome P-450 Enzyme System
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2747-50
references.pmid: 15215142
references.citation: J Exp Med. 1998 Aug 17;188(4):725-34
references.pmid: 9705954
references.citation: J Biol Chem. 1991 Apr 5;266(10):6124-32
references.pmid: 2007571
references.citation: PLoS Negl Trop Dis. 2009;3(2):e372
references.pmid: 19190730
references.citation: Mol Biochem Parasitol. 1987 Nov;26(1-2):1-10
references.pmid: 3323902
references.citation: Int J Cardiol. 2007 Feb 14;115(3):279-83
references.pmid: 16769134
references.citation: Semin Respir Crit Care Med. 2008 Apr;29(2):198-210
references.pmid: 18366001
references.citation: Curr Opin Infect Dis. 2008 Dec;21(6):668-72
references.pmid: 18978536
references.citation: Antimicrob Agents Chemother. 1998 Dec;42(12):3245-50
references.pmid: 9835521
references.citation: Mol Biochem Parasitol. 2003 Dec;132(2):75-81
references.pmid: 14599667
references.citation: J Antimicrob Chemother. 2005 Jan;55(1):31-7
references.pmid: 15563516
references.citation: J Lipid Res. 1989 Oct;30(10):1621-32
references.pmid: 2614264
references.citation: J Clin Microbiol. 2009 Oct;47(10):3142-6
references.pmid: 19692559
references.citation: Emerg Infect Dis. 2009 Jul;15(7):1068-76
references.pmid: 19624922
references.citation: Curr Pharm Des. 2008;14(9):889-900
references.pmid: 18473838
references.citation: PLoS Negl Trop Dis. 2010 Apr 06;4(4):e651
references.pmid: 20386598
references.citation: Mol Biochem Parasitol. 2003 Feb;126(2):129-42
references.pmid: 12615312
references.citation: J Med Chem. 2006 Oct 19;49(21):6177-96
references.pmid: 17034125
references.citation: Am J Health Syst Pharm. 2009 Feb 1;66(3):225-36
references.pmid: 19179636
references.citation: J Med Chem. 2006 Jan 26;49(2):534-53
references.pmid: 16420040
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):3932-9
references.pmid: 17698625
references.citation: Antimicrob Agents Chemother. 2004 Nov;48(11):4405-13
references.pmid: 15504870
references.citation: Antimicrob Agents Chemother. 2004 Feb;48(2):568-74
references.pmid: 14742211
references.citation: J Med Chem. 2004 Mar 25;47(7):1739-49
references.pmid: 15027865
references.citation: Postgrad Med J. 2006 Dec;82(974):788-98
references.pmid: 17148699
references.citation: Antimicrob Agents Chemother. 1998 Jul;42(7):1771-7
references.pmid: 9661019
references.citation: FEMS Yeast Res. 2009 Jun;9(4):626-33
references.pmid: 19385998
references.citation: Antimicrob Agents Chemother. 2007 Apr;51(4):1359-64
references.pmid: 17220408
references.citation: Science. 1996 Aug 16;273(5277):969-71
references.pmid: 8688084
references.citation: Antimicrob Agents Chemother. 2003 Mar;47(3):1120-4
references.pmid: 12604551
references.citation: Antimicrob Agents Chemother. 2008 Jul;52(7):2468-72
references.pmid: 18474574
references.citation: Adv Exp Med Biol. 2008;625:61-80
references.pmid: 18365659
references.citation: Antimicrob Agents Chemother. 2003 May;47(5):1719-26
references.pmid: 12709346
references.citation: Mol Biochem Parasitol. 1985 Sep;16(3):329-43
references.pmid: 3903497
references.citation: Antimicrob Agents Chemother. 2004 Jun;48(6):2124-31
references.pmid: 15155210
references.citation: Antimicrob Agents Chemother. 2003 Feb;47(2):577-81
references.pmid: 12543662
references.citation: Biochem J. 1991 Jul 15;277 ( Pt 2):483-92
references.pmid: 1859375
references.citation: Trends Parasitol. 2005 Nov;21(11):508-12
references.pmid: 16150644
references.citation: J Antimicrob Chemother. 2004 Jan;53(1):74-80
references.pmid: 14657086
references.citation: J Clin Microbiol. 1993 Sep;31(9):2421-6
references.pmid: 8408566
references.citation: Am J Trop Med Hyg. 2010 Apr;82(4):583-7
references.pmid: 20348503
references.citation: Int J Antimicrob Agents. 2003 Jan;21(1):39-48
references.pmid: 12507836
references.citation: J Infect Dis. 1988 Dec;158(6):1408-9
references.pmid: 3143768
references.citation: J Chem Theory Comput. 2007 Mar;3(2):640-8
references.pmid: 26637042
references.citation: Mol Biochem Parasitol. 1999 Oct 25;104(1):81-91
references.pmid: 10589983
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):3915-23
references.pmid: 17846131
references.citation: J Med Chem. 2005 Aug 25;48(17):5415-8
references.pmid: 16107140