title: Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.
abstract: Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.
authors.affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísicia Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, 21941-902, Rio de Janeiro, RJ, Brazil.
authors.forename: Wanderley
authors.initials: W
authors.lastname: de Souza
authors.forename: Juliany Cola Fernandes
authors.initials: JC
authors.lastname: Rodrigues
references.citation: Vet Parasitol. 2007 May 15;146(1-2):25-34
references.pmid: 17367936
references.citation: Science. 1996 Aug 16;273(5277):969-71
references.pmid: 8688084
references.citation: Plant Physiol. 2000 Apr;122(4):1045-56
references.pmid: 10759500
references.citation: Mol Biochem Parasitol. 2002 Nov-Dec;125(1-2):35-45
references.pmid: 12467972
references.citation: Mol Cell Biol. 1989 Aug;9(8):3447-56
references.pmid: 2677674
references.citation: Antimicrob Agents Chemother. 1990 Nov;34(11):2097-105
references.pmid: 2073100
references.citation: Arch Biochem Biophys. 1998 Feb 15;350(2):283-90
references.pmid: 9473303
references.citation: Exp Parasitol. 2005 Dec;111(4):230-8
references.pmid: 16198340
references.citation: Antimicrob Agents Chemother. 2007 Nov;51(11):4049-61
references.pmid: 17709461
references.citation: BMC Microbiol. 2009 Apr 20;9:74
references.pmid: 19379501
references.citation: EMBO J. 2003 Nov 17;22(22):6016-26
references.pmid: 14609948
references.citation: Biochem Biophys Res Commun. 1986 May 14;136(3):851-6
references.pmid: 3521598
references.citation: Chemotherapy. 1996 Jul-Aug;42(4):294-307
references.pmid: 8804798
references.citation: Mol Biochem Parasitol. 2008 Jul;160(1):52-9
references.pmid: 18485498
references.citation: J Biol Chem. 2007 Oct 19;282(42):30804-16
references.pmid: 17724033
references.citation: Protist. 2007 Oct;158(4):447-56
references.pmid: 17719843
references.citation: Biochem Pharmacol. 1996 Jun 14;51(11):1477-87
references.pmid: 8630089
references.citation: J Submicrosc Cytol Pathol. 2003 Jul;35(3):287-94
references.pmid: 14690177
references.citation: Annu Rev Pharmacol Toxicol. 1998;38:375-88
references.pmid: 9597160
references.citation: Mol Biochem Parasitol. 1988 Nov;31(2):149-62
references.pmid: 2847043
references.citation: Antimicrob Agents Chemother. 1984 Apr;25(4):483-7
references.pmid: 6375557
references.citation: Int J Biochem Cell Biol. 2009 Oct;41(10):2069-80
references.pmid: 19379828
references.citation: Curr Pharm Des. 2008;14(9):882-8
references.pmid: 18473837
references.citation: Mol Biochem Parasitol. 2003 Feb;126(2):129-42
references.pmid: 12615312
references.citation: Arch Biochem Biophys. 1976 May;174(1):45-51
references.pmid: 7207
references.citation: Drugs. 2007;67(1):11-6
references.pmid: 17209661
references.citation: Toxicology. 2002 Dec 27;181-182:471-4
references.pmid: 12505355
references.citation: Antimicrob Agents Chemother. 2000 Jan;44(1):150-5
references.pmid: 10602737
references.citation: Int J Antimicrob Agents. 2004 Jul;24(1):72-8
references.pmid: 15225865
references.citation: Bioorg Med Chem. 2005 May 16;13(10):3519-29
references.pmid: 15848765
references.citation: Antimicrob Agents Chemother. 1997 Jul;41(7):1428-32
references.pmid: 9210660
references.citation: J Biol Chem. 1988 Jan 25;263(3):1301-6
references.pmid: 3335546
references.citation: Antimicrob Agents Chemother. 2009 Apr;53(4):1403-10
references.pmid: 19164149
references.citation: J Eukaryot Microbiol. 1995 Jul-Aug;42(4):337-46
references.pmid: 7620457
references.citation: Eukaryot Cell. 2003 Aug;2(4):756-68
references.pmid: 12912895
references.citation: J Med Chem. 2003 Oct 23;46(22):4714-27
references.pmid: 14561091
references.citation: Biochim Biophys Acta. 1995 Sep 13;1238(2):163-76
references.pmid: 7548131
references.citation: J Cell Biol. 1986 Sep;103(3):875-86
references.pmid: 3745272
references.citation: Annu Rev Microbiol. 1995;49:607-39
references.pmid: 8561474
references.citation: FEMS Microbiol Lett. 2006 Feb;255(1):33-42
references.pmid: 16436059
references.citation: Comp Biochem Physiol. 1969 Aug 15;30(4):601-10
references.pmid: 5356613
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2379-87
references.pmid: 15215084
references.citation: Int J Antimicrob Agents. 2004 Mar;23(3):273-85
references.pmid: 15164969
references.citation: Mol Biochem Parasitol. 1984 Feb;10(2):161-70
references.pmid: 6700638
references.citation: Antimicrob Agents Chemother. 1998 Jul;42(7):1771-7
references.pmid: 9661019
references.citation: J Med Chem. 2001 Mar 15;44(6):909-16
references.pmid: 11300872
references.citation: Curr Drug Targets Infect Disord. 2001 May;1(1):51-61
references.pmid: 12455233
references.citation: Antimicrob Agents Chemother. 2002 Feb;46(2):487-99
references.pmid: 11796362
references.citation: Plant Physiol. 1996 Jun;111(2):619-26
references.pmid: 8787029
references.citation: J Biol Chem. 1984 Feb 10;259(3):1661-6
references.pmid: 6420412
references.citation: Biochim Biophys Acta. 2000 Dec 15;1529(1-3):89-102
references.pmid: 11111079
references.citation: Biochem Pharmacol. 1985 Oct 15;34(20):3785-8
references.pmid: 4052119
references.citation: J Eukaryot Microbiol. 2001 Sep-Oct;48(5):588-94
references.pmid: 11596924
references.citation: Antimicrob Agents Chemother. 1999 Dec;43(12):2910-4
references.pmid: 10582881
references.citation: Bioorg Med Chem. 2008 Mar 15;16(6):3283-90
references.pmid: 18096393
references.citation: Int J Antimicrob Agents. 1996 Oct;7(4):235-40
references.pmid: 18611761
references.citation: Parasitology. 1997;114 Suppl:S91-9
references.pmid: 9309771
references.citation: Antimicrob Agents Chemother. 2004 Aug;48(8):2937-50
references.pmid: 15273104
references.citation: Antimicrob Agents Chemother. 2008 Nov;52(11):4098-114
references.pmid: 18765694
references.citation: Antimicrob Agents Chemother. 2002 Mar;46(3):929-31
references.pmid: 11850291
references.citation: J Med Chem. 2006 Feb 9;49(3):892-9
references.pmid: 16451055
references.citation: J Cell Sci. 2005 Jan 15;118(Pt 2):283-90
references.pmid: 15654017
references.citation: Comp Biochem Physiol B. 1972 Jan 15;41(1):1-18
references.pmid: 4561635
references.citation: Mol Biochem Parasitol. 1995 Jul;73(1-2):199-210
references.pmid: 8577328
references.citation: Proc Natl Acad Sci U S A. 1987 Jun;84(12):4012-6
references.pmid: 2438691
references.citation: Antimicrob Agents Chemother. 1988 Aug;32(8):1237-42
references.pmid: 3056256
references.citation: Prog Histochem Cytochem. 2009;44(2):67-124
references.pmid: 19410686
references.citation: Biochem J. 1995 May 15;308 ( Pt 1):31-8
references.pmid: 7755579
references.citation: Nat Rev Microbiol. 2005 Mar;3(3):251-61
references.pmid: 15738951
references.citation: Proc Natl Acad Sci U S A. 1988 Sep;85(18):6753-7
references.pmid: 3413122
references.citation: FEMS Microbiol Lett. 1991 Apr 15;63(2-3):127-31
references.pmid: 2060756
references.citation: Int J Parasitol. 2009 Feb;39(3):307-14
references.pmid: 18848949
references.citation: J Antimicrob Chemother. 2000 Jul;46(1):137-40
references.pmid: 10882704
references.citation: Parasitol Res. 1991;77(6):461-8
references.pmid: 1656428
references.citation: Mol Biochem Parasitol. 2006 Jun;147(2):193-206
references.pmid: 16546274
references.citation: J Lipid Res. 2000 Dec;41(12):1921-35
references.pmid: 11108725
references.citation: J Infect Dis. 2002 Jul 1;186(1):138-40
references.pmid: 12089677
references.citation: Antimicrob Agents Chemother. 1991 Apr;35(4):736-40
references.pmid: 2069380
references.citation: Antimicrob Agents Chemother. 2003 Sep;47(9):2966-70
references.pmid: 12937003
references.citation: Curr Opin Microbiol. 2007 Dec;10(6):539-46
references.pmid: 17997129
references.citation: Antimicrob Agents Chemother. 1993 Mar;37(3):580-91
references.pmid: 8460926
references.citation: Int J Antimicrob Agents. 2004 Mar;23(3):286-90
references.pmid: 15164970
references.citation: Curr Pharm Des. 2008;14(9):925-38
references.pmid: 18473841
references.citation: Micron. 2009 Feb;40(2):157-68
references.pmid: 18849169
references.citation: Mol Biochem Parasitol. 1999 Oct 25;104(1):81-91
references.pmid: 10589983
references.citation: Curr Pharm Des. 2002;8(4):297-318
references.pmid: 11860368
references.citation: J Biol Chem. 1997 Jun 13;272(24):15381-8
references.pmid: 9182568
references.citation: J Med Chem. 1996 Jul 19;39(15):2971-9
references.pmid: 8709131
references.citation: Mol Biochem Parasitol. 1989 Jan 15;32(2-3):179-89
references.pmid: 2494453
references.citation: Prog Lipid Res. 1993;32(4):357-416
references.pmid: 8309949
references.citation: Int J Parasitol. 2001 May 1;31(5-6):472-81
references.pmid: 11334932
references.citation: Annu Rev Microbiol. 1999;53:629-55
references.pmid: 10547703
references.citation: Eukaryot Cell. 2006 Jul;5(7):1057-64
references.pmid: 16835450
references.citation: Rev Recent Clin Trials. 2006 May;1(2):143-53
references.pmid: 18473965
references.citation: Mol Microbiol. 2005 Mar;55(5):1566-78
references.pmid: 15720561
references.citation: Mol Biol Cell. 2004 Mar;15(3):1356-63
references.pmid: 14699057
references.citation: Antimicrob Agents Chemother. 2006 Aug;50(8):2595-601
references.pmid: 16870747
references.citation: Antimicrob Agents Chemother. 2007 Jun;51(6):2123-9
references.pmid: 17371809
references.citation: J Med Chem. 2005 Apr 21;48(8):2957-63
references.pmid: 15828834
references.citation: Mol Biochem Parasitol. 1985 Jun;15(3):257-79
references.pmid: 4033689