Review Article

Major Kinds of Drug Targets in Chagas Disease or American Trypanosomiasis

Author(s): Vilma G. Duschak*

Volume 20, Issue 11, 2019

Page: [1203 - 1216] Pages: 14

DOI: 10.2174/1389450120666190423160804

Price: $65

Abstract

American Trypanosomiasis, a parasitic infection commonly named Chagas disease, affects millions of people all over Latin American countries. Presently, the World Health Organization (WHO) predicts that the number of international infected individuals extends to 7 to 8 million, assuming that more than 10,000 deaths occur annually. The transmission of the etiologic agent, Trypanosoma cruzi, through people migrating to non-endemic world nations makes it an emergent disease. The best promising targets for trypanocidal drugs may be classified into three main groups: Group I includes the main molecular targets that are considered among specific enzymes involved in the essential processes for parasite survival, principally Cruzipain, the major antigenic parasite cysteine proteinase. Group II involves biological pathways and their key specific enzymes, such as Sterol biosynthesis pathway, among others, specific antioxidant defense mechanisms, and bioenergetics ones. Group III includes the atypical organelles /structures present in the parasite relevant clinical forms, which are absent or considerably different from those present in mammals and biological processes related to them. These can be considered potential targets to develop drugs with extra effectiveness and fewer secondary effects than the currently used therapeutics. An improved distinction between the host and the parasite targets will help fight against this neglected disease.

Keywords: Chagas disease, drug targets, groups classification, enzymes, biosynthetic pathways, organelles, Trypanosoma cruzi, target groups.

« Previous
Graphical Abstract

[1]
WHO Chagas disease (American trypanosomiasis). Fact sheet http://www.who.int/mediacentre/factsheets/fs340/en/ [Accessed March, 2016
[2]
Gascon J, Bern C, Pinazo MJ. Chagas disease in Spain, the United States and other non-endemic countries. Acta Trop 2010; 115(1-2): 22-7.
[http://dx.doi.org/10.1016/j.actatropica.2009.07.019] [PMID: 19646412]
[3]
Pérez-Molina JA, Norman F, López-Vélez R. Chagas disease in non-endemic countries: Epidemiology, clinical presentation and treatment. Curr Infect Dis Rep 2012; 14(3): 263-74.
[http://dx.doi.org/10.1007/s11908-012-0259-3] [PMID: 22477037]
[4]
Rassi A Jr, Rassi A, Marcondes de Rezende J. American trypanosomiasis (Chagas disease). Infect Dis Clin North Am 2012; 26(2): 275-91.
[http://dx.doi.org/10.1016/j.idc.2012.03.002] [PMID: 22632639]
[5]
Sesti-Costa R, Silva JS, Gutierrez FR. Congenital Chagas disease: time to screen pregnant women? Expert Rev Anti Infect Ther 2012; 10(11): 1279-82.
[http://dx.doi.org/10.1586/eri.12.122] [PMID: 23241184]
[6]
Kransdorf EP, Zakowski PC, Kobashigawa JA. Chagas disease in solid organ and heart transplantation. Curr Opin Infect Dis 2014; 27(5): 418-24.
[http://dx.doi.org/10.1097/QCO.0000000000000088] [PMID: 25023742]
[7]
Duschak VG. A decade of targets and patented drugs for chemotherapy of Chagas disease. Recent Pat Antiinfect Drug Discov 2011; 6(3): 216-59.
[http://dx.doi.org/10.2174/157489111796887864] [PMID: 21824073]
[8]
Duschak VG. Targets and patented drugs for chemotherapy of Chagas Disease in the Last 15 years-period, review article. Recent Pat Antiinfect Drug Discov 2016; 11(2): 74-173.
[http://dx.doi.org/10.2174/1574891X11666161024165304] [PMID: 27784230]
[9]
Sosa-Estani S, Segura EL. Integrated control of Chagas disease for its elimination as public health problem-a review. Mem Inst Oswaldo Cruz 2015; 110(3): 289-98.
[http://dx.doi.org/10.1590/0074-02760140408] [PMID: 25993503]
[10]
Fernández ML, Marson ME, Ramirez JC, et al. Pharmacokinetic and pharmacodynamic responses in adult patients with Chagas disease treated with a new formulation of benznidazole. Mem Inst Oswaldo Cruz 2016; 111(3): 218-21.
[http://dx.doi.org/10.1590/0074-02760150401] [PMID: 26982179]
[11]
Paucar R, Moreno-Viguri E, Pérez-Silanes S. Challenges in Chagas disease drug discovery: A review. Curr Med Chem 2016; 23(28): 3154-70.
[http://dx.doi.org/10.2174/0929867323999160625124424] [PMID: 27356544]
[12]
Planer JD, Hulverson MA, Arif JA, Ranade RM, Don R, Buckner FS. Synergy testing of FDA-approved drugs identifies potent drug combinations against Trypanosoma cruzi. PLoS Negl Trop Dis 2014; 8(7)e2977
[http://dx.doi.org/10.1371/journal.pntd.0002977] [PMID: 25033456]
[13]
Urbina JA. Recent clinical trials for the etiological treatment of chronic chagas disease: Advances, challenges and perspectives. J Eukaryot Microbiol 2015; 62(1): 149-56.
[http://dx.doi.org/10.1111/jeu.12184] [PMID: 25284065]
[14]
Morillo CA, Waskin H, Sosa-Estani S, et al. Benznidazole and posaconazole in eliminating parasites in asymptomatic T. cruzi carriers: The STOP-CHAGAS Trial. J Am Coll Cardiol 2017; 69(8): 939-47.
[http://dx.doi.org/10.1016/j.jacc.2016.12.023] [PMID: 28231946]
[15]
Duschak VG, Couto AS. Targets and patented drugs for chemotherapy of Chagas disease 2010.
[16]
El-Sayed NM, Myler PJ, Bartholomeu DC, et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease. Science 2005; 309(5733): 409-15.
[http://dx.doi.org/10.1126/science.1112631] [PMID: 16020725]
[17]
Jose Cazzulo J, Stoka V, Turk V. The major cysteine proteinase of Trypanosoma cruzi: A valid target for chemotherapy of Chagas disease. Curr Pharm Des 2001; 7(12): 1143-56.
[http://dx.doi.org/10.2174/1381612013397528] [PMID: 11472258]
[18]
Eakin AE, Mills AA, Harth G, McKerrow JH, Craik CS. The sequence, organization, and expression of the major cysteine protease (cruzain) from Trypanosoma cruzi. J Biol Chem 1992; 267(11): 7411-20.
[PMID: 1559982]
[19]
Cazzulo JJ, Cazzulo Franke MC, Martínez J, Franke de Cazzulo BM. Some kinetic properties of a cysteine proteinase (cruzipain) from Trypanosoma cruzi. Biochim Biophys Acta 1990; 1037(2): 186-91.
[http://dx.doi.org/10.1016/0167-4838(90)90166-D] [PMID: 2407295]
[20]
Murta ACM, Persechini PM, Padron Tde S, de Souza W, Guimarães JA, Scharfstein J. Structural and functional identification of GP57/51 antigen of Trypanosoma cruzi as a cysteine proteinase. Mol Biochem Parasitol 1990; 43(1): 27-38.
[http://dx.doi.org/10.1016/0166-6851(90)90127-8] [PMID: 1705310]
[21]
Alvarez VE, Niemirowicz GT, Cazzulo JJ. The peptidases of Trypanosoma cruzi: digestive enzymes, virulence factors, and mediators of autophagy and programmed cell death. Biochim Biophys Acta 2012; 1824(1): 195-206.
[http://dx.doi.org/10.1016/j.bbapap.2011.05.011] [PMID: 21621652]
[22]
Cazzulo JJ, Labriola C, Parussini F, Duschak VG, Martinez J, de Cazzulo FBM. Cysteine proteinases in Trypanosoma cruzi and other Trypanosomatid parasites. Acta Chim Slov 1995; 42: 409-18.
[23]
Parussini F, Duschak VG, Cazzulo JJ. Membrane-bound cysteine proteinase isoforms in different developmental stages of Trypanosoma cruzi. Cell Mol Biol 1998; 44(3): 513-9.
[PMID: 9620448]
[24]
Duschak VG, Barboza M, García GA, Lammel EM, Couto AS, Isola EL. Novel cysteine proteinase in Trypanosoma cruzi metacyclogenesis. Parasitology 2006; 132(Pt 3): 345-55.
[http://dx.doi.org/10.1017/S0031182005009030] [PMID: 16238824]
[25]
Duschak VG, Ciaccio M, Nassert JR, Basombrio MA. Enzymatic activity, protein expression, and gene sequence of cruzipain in virulent and attenuated Trypanosoma cruzi strains. J Parasitol 2001; 87(5): 1016-22.
[http://dx.doi.org/10.1645/0022-3395(2001)087[1016:EAPEAG]2.0.CO;2] [PMID: 11695358]
[26]
Ramos AM, Duschak VG, Gerez de Burgos NM, et al. Trypanosoma cruzi: Cruzipain and membrane-bound cysteine proteinase isoform(s) interacts with human alpha(2)-macroglobulin and pregnancy zone protein. Exp Parasitol 2002; 100(2): 121-30.
[http://dx.doi.org/10.1016/S0014-4894(02)00007-3] [PMID: 12054702]
[27]
Duschak VG, Riarte A, Segura EL, Laucella SA. Humoral immune response to cruzipain and cardiac dysfunction in chronic Chagas disease. Immunol Lett 2001; 78(3): 135-42.
[http://dx.doi.org/10.1016/S0165-2478(01)00255-3] [PMID: 11578687]
[28]
Duschak VG, Couto AS. Cruzipain, the major cysteine protease of Trypanosoma cruzi: A sulfated glycoprotein antigen as relevant candidate for vaccine development and drug target. A review. Curr Med Chem 2009; 16(24): 3174-202.
[http://dx.doi.org/10.2174/092986709788802971] [PMID: 19689291]
[29]
Lima AP, Reis FC, Costa TF. Cysteine peptidase inhibitors in trypanosomatid parasites. Curr Med Chem 2013; 20(25): 3152-73.
[http://dx.doi.org/10.2174/0929867311320250009] [PMID: 23514421]
[30]
Branquinha MH, Oliveira SS, Sangenito LS, et al. Cruzipain: An update on its potential as chemotherapy target against the human pathogen Trypanosoma cruzi. Curr Med Chem 2015; 22(18): 2225-35.
[http://dx.doi.org/10.2174/0929867322666150521091652] [PMID: 25994861]
[31]
Sajid M, Robertson SA, Brinen LS, McKerrow JH. Cruzain: the path from target validation to the clinic. Adv Exp Med Biol 2011; 712: 100-15.
[http://dx.doi.org/10.1007/978-1-4419-8414-2_7] [PMID: 21660661]
[32]
Bellera CL, Balcazar DE, Alberca L, Labriola CA, Talevi A, Carrillo C. Application of computer-aided drug repurposing in the search of new cruzipain inhibitors: Discovery of amiodarone and bromocriptine inhibitory effects. J Chem Inf Model 2013; 53(9): 2402-8.
[http://dx.doi.org/10.1021/ci400284v] [PMID: 23906322]
[33]
Salas-Sarduy E, Urán Landaburu L, Karpiak J, et al. Novel scaffolds for inhibition of cruzipain identified from high throughput screening of antikinetoplastid chemical boxes. Sci Rep 2018; 8(1): 8743.
[http://dx.doi.org/10.1038/s41598-018-26961-w] [PMID: 29867193]
[34]
Goll DE, Thompson VF, Li H, Wei W, Cong J. The calpain system. Physiol Rev 2003; 83(3): 731-801.
[http://dx.doi.org/10.1152/physrev.00029.2002] [PMID: 12843408]
[35]
Kosec G, Alvarez V, Cazzulo JJ. Cysteine proteinases of Trypanosoma cruzi: From digestive enzymes to programmed cell death mediators. Biocell 2006; 30(3): 479-90.
[PMID: 17375468]
[36]
Branquinha MH, Marinho FA, Sangenito LS, et al. Calpains: potential targets for alternative chemotherapeutic intervention against human pathogenic trypanosomatids. Curr Med Chem 2013; 20(25): 3174-85.
[http://dx.doi.org/10.2174/0929867311320250010] [PMID: 23899207]
[37]
Urbina JA. Recent clinical trials for the etiological treatment of chronic chagas disease: Advances, challenges and perspectives. J Eukaryot Microbiol 2015; 62(1): 149-56.
[http://dx.doi.org/10.1111/jeu.12184] [PMID: 25284065]
[38]
Quiñones W, Urbina JA, Dubourdieu M, Luis Concepción J. The glycosome membrane of Trypanosoma cruzi epimastigotes: protein and lipid composition. Exp Parasitol 2004; 106(3-4): 135-49.
[http://dx.doi.org/10.1016/j.exppara.2004.03.006] [PMID: 15172221]
[39]
Urbina JA. Chemotherapy of Chagas disease. Curr Pharm Des 2002; 8(4): 287-95.
[http://dx.doi.org/10.2174/1381612023396177] [PMID: 11860367]
[40]
Lepesheva GI, Ott RD, Hargrove TY, et al. Sterol 14alpha-demethylase as a potential target for antitrypanosomal therapy: Enzyme inhibition and parasite cell growth. Chem Biol 2007; 14(11): 1283-93.
[http://dx.doi.org/10.1016/j.chembiol.2007.10.011] [PMID: 18022567]
[41]
Hankins EG, Gillespie JR, Aikenhead K, Buckner FS. Upregulation of sterol C14-demethylase expression in Trypanosoma cruzi treated with sterol biosynthesis inhibitors. Mol Biochem Parasitol 2005; 144(1): 68-75.
[http://dx.doi.org/10.1016/j.molbiopara.2005.08.002] [PMID: 16165233]
[42]
Lepesheva GI, Hargrove TY, Anderson S, et al. Structural insights into inhibition of sterol 14alpha-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem 2010; 285(33): 25582-90.
[http://dx.doi.org/10.1074/jbc.M110.133215] [PMID: 20530488]
[43]
Hargrove TY, Wawrzak Z, Liu J, Waterman MR, Nes WD, Lepesheva GI. Structural complex of sterol 14α-demethylase (CYP51) with 14α-methylenecyclopropyl-Delta7-24, 25-dihydrolanosterol. J Lipid Res 2012; 53(2): 311-20.
[http://dx.doi.org/10.1194/jlr.M021865] [PMID: 22135275]
[44]
Gunatilleke SS, Calvet CM, Johnston JB, et al. Diverse inhibitor chemotypes targeting Trypanosoma cruzi CYP51. PLoS Negl Trop Dis 2012; 6(7)e1736
[http://dx.doi.org/10.1371/journal.pntd.0001736] [PMID: 22860142]
[45]
Urbina JA. New advances in the management of a long-neglected disease. Clin Infect Dis 2009; 49(11): 1685-7.
[http://dx.doi.org/10.1086/648073] [PMID: 19877968]
[46]
Molina I, Gómez i Prat J, Salvador F, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med 2014; 370(20): 1899-908.
[http://dx.doi.org/10.1056/NEJMoa1313122] [PMID: 24827034]
[47]
Urbina JA. The long road towards a safe and effective treatment of chronic Chagas disease. Lancet Infect Dis 2018; 18(4): 363-5.
[http://dx.doi.org/10.1016/S1473-3099(17)30535-2] [PMID: 29352705]
[48]
Joubert BM, Buckner FS, Matsuda SP. Trypanosome and animal lanosterol synthases use different catalytic motifs. Org Lett 2001; 3(12): 1957-60.
[http://dx.doi.org/10.1021/ol0160506] [PMID: 11405754]
[49]
Lange S, Keller M, Müller C, Oliaro-Bosso S, Balliano G, Bracher F. Aminopropylindenes derived from Grundmann’s ketone as a novel chemotype of oxidosqualene cyclase inhibitors. Eur J Med Chem 2013; 63: 758-64.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.002] [PMID: 23583910]
[50]
Galli U, Oliaro-Bosso S, Taramino S, et al. Design, synthesis, and biological evaluation of new (2E,6E)-10-(dimethylamino)-3,7dimethyl-2,6-decadien-1-ol ethers as inhibitors of human and oxidosqualene cyclase. Bioorg Med Chem Lett 2007; 17: 220-4.
[http://dx.doi.org/10.1016/j.bmcl.2006.09.058] [PMID: 17027267]
[51]
Urbina JA, Lazardi K, Aguirre T, Piras MM, Piras R. Antiproliferative synergism of the allylamine SF 86-327 and ketoconazole on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrob Agents Chemother 1988; 32(8): 1237-42.
[http://dx.doi.org/10.1128/AAC.32.8.1237] [PMID: 3056256]
[52]
Lazardi K, Urbina JA, de Souza W. Ultrastructural alterations induced by two ergosterol biosynthesis inhibitors, ketoconazole and terbinafine, on epimastigotes and amastigotes of Trypanosoma (Schizotrypanum) cruzi. Antimicrob Agents Chemother 1990; 34(11): 2097-105.
[http://dx.doi.org/10.1128/AAC.34.11.2097] [PMID: 2073100]
[53]
Gerpe A, Alvarez G, Benítez D, et al. 5-Nitrofuranes and 5-nitrothiophenes with anti-Trypanosoma cruzi activity and ability to accumulate squalene. Bioorg Med Chem 2009; 17(21): 7500-9.
[http://dx.doi.org/10.1016/j.bmc.2009.09.013] [PMID: 19811923]
[54]
Urbina JA, Concepcion JL, Rangel S, Visbal G, Lira R. Squalene synthase as a chemotherapeutic target in Trypanosoma cruzi and Leishmania mexicana. Mol Biochem Parasitol 2002; 125(1-2): 35-45.
[http://dx.doi.org/10.1016/S0166-6851(02)00206-2] [PMID: 12467972]
[55]
Urbina JA, Payares G, Sanoja C, et al. Parasitological cure of acute and chronic experimental Chagas disease using the long-acting experimental triazole TAK-187. Activity against drug-resistant Trypanosoma cruzi strains. Int J Antimicrob Agents 2003; 21(1): 39-48.
[http://dx.doi.org/10.1016/S0924-8579(02)00274-1] [PMID: 12507836]
[56]
Veiga-Santos P, Li K, Lameira L, et al. SQ109, a new drug lead for Chagas disease. Antimicrob Agents Chemother 2015; 59(4): 1950-61.
[http://dx.doi.org/10.1128/AAC.03972-14] [PMID: 25583723]
[57]
Urbina JA, Concepción JL, Caldera A, et al. In vitro and in vivo activities of E5700 and ER-119884, two novel orally active squalene synthase inhibitors, against Trypanosoma cruzi. Antimicrob Agents Chemother 2004; 48(7): 2379-87.
[http://dx.doi.org/10.1128/AAC.48.7.2379-2387.2004] [PMID: 15215084]
[58]
Sealey-Cardona M, Cammerer S, Jones S, et al. Kinetic characterization of squalene synthase from Trypanosoma cruzi: Selective inhibition by quinuclidine derivatives. Antimicrob Agents Chemother 2007; 51(6): 2123-9.
[http://dx.doi.org/10.1128/AAC.01454-06] [PMID: 17371809]
[59]
Shang N, Li Q, Ko TP, et al. Squalene synthase as a target for Chagas disease therapeutics. PLoS Pathog 2014; 10(5)e1004114
[http://dx.doi.org/10.1371/journal.ppat.1004114] [PMID: 24789335]
[60]
Lorente SO, Jimenez CJ, Gros L, et al. Preparation of transition-state analogues of sterol 24-methyl transferase as potential anti-parasitics. Bioorg Med Chem 2005; 13(18): 5435-53.
[http://dx.doi.org/10.1016/j.bmc.2005.06.012] [PMID: 16046134]
[61]
Braga MV, Magaraci F, Lorente SO, Gilbert I, de Souza W. Effects of inhibitors of Delta24(25)-sterol methyl transferase on the ultrastructure of epimastigotes of Trypanosoma cruzi. Microsc Microanal 2005; 11(6): 506-15.
[http://dx.doi.org/10.1017/S143192760505035X] [PMID: 17481329]
[62]
Peña-Diaz J, Montalvetti A, Flores CL, et al. Mitochondrial localization of the mevalonate pathway enzyme 3-Hydroxy-3-methyl-glutaryl-CoA reductase in the Trypanosomatidae. Mol Biol Cell 2004; 15(3): 1356-63.
[http://dx.doi.org/10.1091/mbc.e03-10-0720] [PMID: 14699057]
[63]
Urbina JA, Lazardi K, Marchan E, et al. Mevinolin (lovastatin) potentiates the antiproliferative effects of ketoconazole and terbinafine against Trypanosoma (Schizotrypanum) cruzi: In vitro and in vivo studies. Antimicrob Agents Chemother 1993; 37(3): 580-91.
[http://dx.doi.org/10.1128/AAC.37.3.580] [PMID: 8460926]
[64]
Concepcion JL, Gonzalez-Pacanowska D, Urbina JA. 3-Hydroxy-3-methyl-glutaryl-CoA reductase in Trypanosoma (Schizotrypanum) cruzi: Subcellular localization and kinetic properties. Arch Biochem Biophys 1998; 352(1): 114-20.
[http://dx.doi.org/10.1006/abbi.1998.0577] [PMID: 9521823]
[65]
Hurtado-Guerrrero R, Peña-Díaz J, Montalvetti A, Ruiz-Pérez LM, González-Pacanowska D. Kinetic properties and inhibition of Trypanosoma cruzi 3-hydroxy-3-methylglutaryl CoA reductase. FEBS Lett 2002; 510(3): 141-4.
[http://dx.doi.org/10.1016/S0014-5793(01)03238-0] [PMID: 11801242]
[66]
Ferella M, Li ZH, Andersson B, Docampo R. Farnesyl diphosphate synthase localizes to the cytoplasm of Trypanosoma cruzi and T. brucei. Exp Parasitol 2008; 119(2): 308-12.
[http://dx.doi.org/10.1016/j.exppara.2008.02.013] [PMID: 18406406]
[67]
Montalvetti A, Bailey BN, Martin MB, Severin GW, Oldfield E, Docampo R. Bisphosphonates are potent inhibitors of Trypanosoma cruzi farnesyl pyrophosphate synthase. J Biol Chem 2001; 276(36): 33930-7.
[http://dx.doi.org/10.1074/jbc.M103950200] [PMID: 11435429]
[68]
Martin MB, Grimley JS, Lewis JC, et al. Bisphosphonates inhibit the growth of Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondii, and Plasmodium falciparum: A potential route to chemotherapy. J Med Chem 2001; 44(6): 909-16.
[http://dx.doi.org/10.1021/jm0002578] [PMID: 11300872]
[69]
Garzoni LR, Caldera A, Meirelles Mde N, et al. Selective in vitro effects of the farnesyl pyrophosphate synthase inhibitor risedronate on Trypanosoma cruzi. Int J Antimicrob Agents 2004; 23(3): 273-85.
[http://dx.doi.org/10.1016/j.ijantimicag.2003.07.020] [PMID: 15164969]
[70]
Docampo R, Moreno SN. Bisphosphonates as chemotherapeutic agents against trypanosomatid and apicomplexan parasites. Curr Drug Targets Infect Disord 2001; 1(1): 51-61.
[http://dx.doi.org/10.2174/1568005013343191] [PMID: 12455233]
[71]
Szajnman SH, Ravaschino EL, Docampo R, Rodriguez JB. Synthesis and biological evaluation of 1-amino-1,1-bisphosphonates derived from fatty acids against Trypanosoma cruzi targeting farnesyl pyrophosphate synthase. Bioorg Med Chem Lett 2005; 15(21): 4685-90.
[http://dx.doi.org/10.1016/j.bmcl.2005.07.060] [PMID: 16143525]
[72]
Sigman L, Sánchez VM, Turjanski AG. Characterization of the farnesyl pyrophosphate synthase of Trypanosoma cruzi by homology modeling and molecular dynamics. J Mol Graph Model 2006; 25(3): 345-52.
[http://dx.doi.org/10.1016/j.jmgm.2006.02.001] [PMID: 16540358]
[73]
Recher M, Barboza AP, Li ZH, et al. Design, synthesis and biological evaluation of sulfur-containing 1,1-bisphosphonic acids as antiparasitic agents. Eur J Med Chem 2013; 60: 431-40.
[http://dx.doi.org/10.1016/j.ejmech.2012.12.015] [PMID: 23318904]
[74]
Esteva MI, Kettler K, Maidana C, et al. Benzophenone-based farnesyltransferase inhibitors with high activity against Trypanosoma cruzi. J Med Chem 2005; 48(23): 7186-91.
[http://dx.doi.org/10.1021/jm050456x] [PMID: 16279776]
[75]
Augustyns K, Amssoms K, Yamani A, Rajan PK, Haemers A. Trypanothione as a target in the design of antitrypanosomal and antileishmanial agents. Curr Pharm Des 2001; 7(12): 1117-41.
[http://dx.doi.org/10.2174/1381612013397564] [PMID: 11472257]
[76]
Leroux AE, Krauth-Siegel RL. Thiol redox biology of trypanosomatids and potential targets for chemotherapy 2015.
[77]
Krauth-Siegel RL, Bauer H, Schirmer RH. Dithiol proteins as guardians of the intracellular redox milieu in parasites: Old and new drug targets in trypanosomes and malaria-causing plasmodia. Angew Chem Int Ed Engl 2005; 44(5): 690-715.
[http://dx.doi.org/10.1002/anie.200300639] [PMID: 15657967]
[78]
Faundez M, Pino L, Letelier P, et al. Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi. Antimicrob Agents Chemother 2005; 49(1): 126-30.
[http://dx.doi.org/10.1128/AAC.49.1.126-130.2005] [PMID: 15616285]
[79]
Stoppani AO. The chemotherapy of Chagas disease 1999.
[80]
Lo Presti MS, Bazán PC, Strauss M, Báez AL, Rivarola HW, Paglini-Oliva PA. Trypanothione reductase inhibitors: Overview of the action of thioridazine in different stages of Chagas disease. Acta Trop 2015; 145: 79-87.
[http://dx.doi.org/10.1016/j.actatropica.2015.02.012] [PMID: 25733492]
[81]
Souza DH, Garratt RC, Araújo AP, et al. Trypanosoma cruzi glycosomal glyceraldehyde-3-phosphate dehydrogenase: Structure, catalytic mechanism and targeted inhibitor design. FEBS Lett 1998; 424(3): 131-5.
[http://dx.doi.org/10.1016/S0014-5793(98)00154-9] [PMID: 9580189]
[82]
Lakhdar-Ghazal F, Blonski C, Willson M, Michels P, Perie J. Glycolysis and proteases as targets for the design of new anti-trypanosome drugs. Curr Top Med Chem 2002; 2(5): 439-56.
[http://dx.doi.org/10.2174/1568026024607472] [PMID: 11966466]
[83]
Bressi JC, Verlinde CL, Aronov AM, et al. Adenosine analogues as selective inhibitors of glyceraldehyde-3-phosphate dehydrogenase of Trypanosomatidae via structure-based drug design. J Med Chem 2001; 44(13): 2080-93.
[http://dx.doi.org/10.1021/jm000472o] [PMID: 11405646]
[84]
Maluf FV, Andricopulo AD, Oliva G, Guido RV. A pharmacophore-based virtual screening approach for the discovery of Trypanosoma cruzi GAPDH inhibitors. Future Med Chem 2013; 5(17): 2019-35.
[http://dx.doi.org/10.4155/fmc.13.166] [PMID: 24215344]
[85]
Barros-Alvarez X, Gualdrón-López M, Acosta H, et al. Glycosomal targets for anti-trypanosomatid drug discovery. Curr Med Chem 2014; 21(15): 1679-706.
[http://dx.doi.org/10.2174/09298673113209990139] [PMID: 23834165]
[86]
Pariona-Llanos R, Pavani RS, Reis M, et al. Glyceraldehyde 3-phosphate dehydrogenase-telomere association correlates with redox status in Trypanosoma cruzi. PLoS One 2015; 10(3)e0120896
[http://dx.doi.org/10.1371/journal.pone.0120896] [PMID: 25775131]
[87]
Gupta S, Cordeiro AT, Michels PA. Glucose-6-phosphate dehydrogenase is the target for the trypanocidal action of human steroids. Mol Biochem Parasitol 2011; 176(2): 112-5.
[http://dx.doi.org/10.1016/j.molbiopara.2010.12.006] [PMID: 21185333]
[88]
Cordeiro AT, Thiemann OH. 16-bromoepiandrosterone, an activator of the mammalian immune system, inhibits glucose 6-phosphate dehydrogenase from Trypanosoma cruzi and is toxic to these parasites grown in culture. Bioorg Med Chem 2010; 18(13): 4762-8.
[http://dx.doi.org/10.1016/j.bmc.2010.05.008] [PMID: 20570159]
[89]
Mercaldi GF, Ranzani AT, Cordeiro AT. Discovery of new uncompetitive inhibitors of glucose-6-phosphate dehydrogenase. J Biomol Screen 2014; 19(10): 1362-71.
[http://dx.doi.org/10.1177/1087057114546896] [PMID: 25121555]
[90]
Maugeri DA, Cazzulo JJ. The pentose phosphate pathway in Trypanosoma cruzi. FEMS Microbiol Lett 2004; 234(1): 117-23.
[http://dx.doi.org/10.1111/j.1574-6968.2004.tb09522.x] [PMID: 15109729]
[91]
Igoillo-Esteve M, Maugeri D, Stern AL, Beluardi P, Cazzulo JJ. The pentose phosphate pathway in Trypanosoma cruzi: a potential target for the chemotherapy of Chagas disease. An Acad Bras Cienc 2007; 79(4): 649-63.
[http://dx.doi.org/10.1590/S0001-37652007000400007] [PMID: 18066434]
[92]
Rassi A, Luquetti AO, Rassi A Jr, et al. Specific treatment for Trypanosoma cruzi: Lack of efficacy of allopurinol in the human chronic phase of Chagas disease. Am J Trop Med Hyg 2007; 76(1): 58-61.
[http://dx.doi.org/10.4269/ajtmh.2007.76.58] [PMID: 17255230]
[93]
Freymann DM, Wenck MA, Engel JC, et al. Efficient identification of inhibitors targeting the closed active site conformation of the HPRT from Trypanosoma cruzi. Chem Biol 2000; 7(12): 957-68.
[http://dx.doi.org/10.1016/S1074-5521(00)00045-4] [PMID: 11137818]
[94]
Wenck MA, Medrano FJ, Eakin AE, Craig SP. Steady-state kinetics of the hypoxanthine phosphoribosyltransferase from Trypanosoma cruzi. Biochim Biophys Acta 2004; 1700(1): 11-8.
[http://dx.doi.org/10.1016/j.bbapap.2004.03.009] [PMID: 15210120]
[95]
Reche P, Arrebola R, Santi DV, Gonzalez-Pacanowska D, Ruiz-Perez LM. Expression and characterization of the Trypanosoma cruzi dihydrofolate reductase domain. Mol Biochem Parasitol 1996; 76(1-2): 175-85.
[http://dx.doi.org/10.1016/0166-6851(95)02557-X] [PMID: 8920005]
[96]
Gilbert IH. Inhibitors of dihydrofolate reductase in Leishmania and trypanosomes. Biochim Biophys Acta 2002; 1587(2-3): 249-57.
[http://dx.doi.org/10.1016/S0925-4439(02)00088-1] [PMID: 12084467]
[97]
Schormann N, Velu SE, Murugesan S, et al. Synthesis and characterization of potent inhibitors of Trypanosoma cruzi dihydrofolate reductase. Bioorg Med Chem 2010; 18(11): 4056-66.
[http://dx.doi.org/10.1016/j.bmc.2010.04.020] [PMID: 20452776]
[98]
Panecka-Hofman J, Pöhner I, Spyrakis F, et al. Comparative mapping of on-targets and off-targets for the discovery of anti-trypanosomatid folate pathway inhibitors. Biochim Biophys Acta, Gen Subj 2017; 1861(12): 3215-30.
[99]
Cavazzuti A, Paglietti G, Hunter WN, et al. Discovery of potent pteridine reductase inhibitors to guide antiparasite drug development. Proc Natl Acad Sci USA 2008; 105(5): 1448-53.
[http://dx.doi.org/10.1073/pnas.0704384105] [PMID: 18245389]
[100]
Souza Wd. Structural organization of Trypanosoma cruzi. Mem Inst Oswaldo Cruz 2009; 104(Suppl. 1): 89-100.
[http://dx.doi.org/10.1590/S0074-02762009000900014] [PMID: 19753463]
[101]
Portman N, Gull K. The paraflagellar rod of kinetoplastid parasites: from structure to components and function. Int J Parasitol 2010; 40(2): 135-48.
[http://dx.doi.org/10.1016/j.ijpara.2009.10.005] [PMID: 19879876]
[102]
Docampo R, Jimenez V, King-Keller S, Li ZH, Moreno SN. The role of acidocalcisomes in the stress response of Trypanosoma cruzi. Adv Parasitol 2011; 75: 307-24.
[http://dx.doi.org/10.1016/B978-0-12-385863-4.00014-9] [PMID: 21820562]
[103]
Hannaert V, Bringaud F, Opperdoes FR, Michels PA. Evolution of energy metabolism and its compartmentation in Kinetoplastida. Kinetoplastid Biol Dis 2003; 2(1): 11-41.
[http://dx.doi.org/10.1186/1475-9292-2-11] [PMID: 14613499]
[104]
Volpato H, Desoti VC, Valdez RH, et al. Mitochondrial dysfunction induced by N-butyl-1-(4-dimethylamino) phenyl-1,2,3,4tetrahydro-β-carboline-3-carboxamide is required for cell death of Trypanosoma cruzi. PLoS One 2015; 10(6)e0130652
[http://dx.doi.org/10.1371/journal.pone.0130652] [PMID: 26086449]
[105]
Dantas AP, Barbosa HS, De Castro SL. Biological and ultrastructural effects of the anti-microtubule agent taxol against Trypanosoma cruzi. J Submicrosc Cytol Pathol 2003; 35(3): 287-94.
[PMID: 14690177]
[106]
Bisaggio DF, Adade CM, Souto-Padrón T. In vitro effects of suramin on Trypanosoma cruzi. Int J Antimicrob Agents 2008; 31(3): 282-6.
[http://dx.doi.org/10.1016/j.ijantimicag.2007.11.001] [PMID: 18191547]
[107]
Potenza M, Tellez-Iñón MT. Colchicine treatment reversibly blocks cytokinesis but not mitosis in Trypanosoma cruzi epimastigotes. Parasitol Res 2015; 114(2): 641-9.
[http://dx.doi.org/10.1007/s00436-014-4227-8] [PMID: 25407128]
[108]
Souto-Padron T, Cunha e Silva NL, de Souza W. Acetylated alpha-tubulin in Trypanosoma cruzi: Immunocytochemical localization. Mem Inst Oswaldo Cruz 1993; 88(4): 517-28.
[http://dx.doi.org/10.1590/S0074-02761993000400004] [PMID: 8139463]
[109]
Silva CF, Meuser MB, De Souza EM, et al. Cellular effects of reversed amidines on Trypanosoma cruzi. Antimicrob Agents Chemother 2007; 51(11): 3803-9.
[http://dx.doi.org/10.1128/AAC.00047-07] [PMID: 17698624]
[110]
Durante IM, Cámara M de L, Buscaglia CA. A novel Trypanosoma cruziprotein associated to the flagellar pocket of replicative stages and involved in parasite growth. PLoS One 2015; 10(6)e0130099
[http://dx.doi.org/10.1371/journal.pone.0130099] [PMID: 26086767]
[111]
Docampo R, de Souza W, Miranda K, Rohloff P, Moreno SN. Acidocalcisomes - conserved from bacteria to man. Nat Rev Microbiol 2005; 3(3): 251-61.
[http://dx.doi.org/10.1038/nrmicro1097] [PMID: 15738951]
[112]
Docampo R, Moreno SN. The acidocalcisome as a target for chemotherapeutic agents in protozoan parasites. Curr Pharm Des 2008; 14(9): 882-8.
[http://dx.doi.org/10.2174/138161208784041079] [PMID: 18473837]
[113]
Gabelli SB, McLellan JS, Montalvetti A, Oldfield E, Docampo R, Amzel LM. Structure and mechanism of the farnesyl diphosphate synthase from Trypanosoma cruzi: implications for drug design. Proteins 2006; 62(1): 80-8.
[http://dx.doi.org/10.1002/prot.20754] [PMID: 16288456]
[114]
Veiga-Santos P, Barrias ES, Santos JF, et al. Effects of amiodarone and posaconazole on the growth and ultrastructure of Trypanosoma cruzi. Int J Antimicrob Agents 2012; 40(1): 61-71.
[http://dx.doi.org/10.1016/j.ijantimicag.2012.03.009] [PMID: 22591838]
[115]
Docampo R, Jimenez V, Lander N, Li ZH, Niyogi S. New insights into roles of acidocalcisomes and contractile vacuole complex in osmoregulation in protists. Int Rev Cell Mol Biol 2013; 305: 69-113.
[http://dx.doi.org/10.1016/B978-0-12-407695-2.00002-0] [PMID: 23890380]
[116]
Landfear SM. Drugs and transporters in kinetoplastid protozoa. Adv Exp Med Biol 2008; 625: 22-32.
[http://dx.doi.org/10.1007/978-0-387-77570-8_3] [PMID: 18365656]
[117]
Taylor MC, Lewis MD, Fortes Francisco A, Wilkinson SR, Kelly JM. The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence. PLoS Negl Trop Dis 2015; 9(4)e0003707
[http://dx.doi.org/10.1371/journal.pntd.0003707] [PMID: 25875298]
[118]
Duschak VD. Advances in the neglected Chagas Disease: Drug targets and trypanocide compounds. Curr Trends Biomedical Eng Biosci 2017; 6(4): 1-3.
[http://dx.doi.org/10.19080/CTBEB.2017.06.555693]
[119]
Kamina AD, Williams N. Ribosome Assembly in Trypanosomatids: A novel therapeutic target. Trends Parasitol 2017; 33(4): 256-7.
[http://dx.doi.org/10.1016/j.pt.2016.12.003] [PMID: 27988096]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy