Heme metabolism as a therapeutic target against protozoan parasites

References

• Hotez PJ, Alvarado M, Basáñez M-G. The global burden of disease study 2010: interpretation and implications for the neglected tropical diseases. PLoS Negl Trop Dis. 2014;8:e2865.
   PubMed Web of Science ®Google Scholar
• Lozano R, Naghavi M, Foreman K. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128.
   PubMed Web of Science ®Google Scholar
• Hotez PJ, Molyneux DH, Fenwick A, et al. Control of neglected tropical diseases. N Engl J Med. 2007;357:1018–1027.
   PubMed Web of Science ®Google Scholar
• Røttingen J-A, Regmi S, Eide M, et al. Mapping of available health research and development data: what's there, what's missing, and what role is there for a global observatory?. Lancet. 2013;382:1286–1307.
   PubMed Web of Science ®Google Scholar
• Pedrique B, Strub-Wourgaft N, Some C, et al. The drug and vaccine landscape for neglected diseases (2000–11): a systematic assessment. Lancet Glob Heal. 2013;1:e371–e379.
   PubMed Web of Science ®Google Scholar
• Bhutta ZA, Sommerfeld J, Lassi ZS, et al. Global burden, distribution, and interventions for infectious diseases of poverty. Infect Dis Poverty. 2014;3:21.
   PubMed Web of Science ®Google Scholar
• Nwaka S, Hudson A. Innovative lead discovery strategies for tropical diseases. Nat Rev Drug Discov. 2006;5:941–955.
   PubMed Web of Science ®Google Scholar
• Renslo AR, McKerrow JH. Drug discovery and development for neglected parasitic diseases. Nat Chem Biol. 2006;2:701–710.
   PubMed Web of Science ®Google Scholar
• Pink R, Hudson A, Mouriès M-A, et al. Opportunities and challenges in antiparasitic drug discovery. Nat Rev Drug Discov. 2005;4:727–740.
   PubMed Web of Science ®Google Scholar
• Gilbert IH. Drug discovery for neglected diseases: molecular target-based and phenotypic approaches. J Med Chem. 2013;56:7719–7726.
   PubMed Web of Science ®Google Scholar
• Gorka AP, de Dios A, Roepe PD. Quinoline drug-heme interactions and implications for antimalarial cytostatic versus cytocidal activities. J Med Chem. 2013;56:5231–5246.
   PubMed Web of Science ®Google Scholar
• Choi JY, Calvet CM, Gunatilleke SS, et al. Rational development of 4-aminopyridyl-based inhibitors targeting Trypanosoma cruzi CYP51 as anti-chagas agents. J Med Chem. 2013;56:7651–7668.
   PubMed Web of Science ®Google Scholar
• Pamplona A, Ferreira A, Balla J, et al. Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med. 2007;13:703–710.
   PubMed Web of Science ®Google Scholar
• Harris F, Pierpoint L. Photodynamic therapy based on 5-aminolevulinic acid and its use as an antimicrobial agent. Med Res Rev. 2012;32:1292–1327.
   PubMed Web of Science ®Google Scholar
• Ponka P. Cell biology of heme. Am J Med Sci. 1999;318:241–256.
   PubMed Web of Science ®Google Scholar
• Kořený L, Oborník M, Lukeš J. Make it, take it, or leave it: heme metabolism of parasites. PLoS Pathog. 2013;9:e1003088.
   PubMed Web of Science ®Google Scholar
• Toh SQ, Glanfield A, Gobert GN, et al. Heme and blood-feeding parasites: friends or foes? Parasit Vectors. 2010;3:108.
   PubMed Web of Science ®Google Scholar
• Tripodi KE, Menendez Bravo SM, Cricco JA. Role of heme and heme-proteins in trypanosomatid essential metabolic pathways. Enzyme Res. 2011;2011:1.
   Google Scholar
• Bonday ZQ, Dhanasekaran S, Rangarajan PN, et al. Import of host delta-aminolevulinate dehydratase into the malarial parasite: identification of a new drug target. Nat Med. 2000;6:898–903.
   PubMed Web of Science ®Google Scholar
• Sigala P. a, Goldberg DE. The peculiarities and paradoxes of plasmodium heme metabolism. Annu Rev Microbiol. 2014;68:259–278.
   PubMed Web of Science ®Google Scholar
• Kehrer JP. The Haber-Weiss reaction and mechanisms of toxicity. Toxicology. 2000;149:43–50.
   PubMed Web of Science ®Google Scholar
• Vincent SH. Oxidative effects of heme and porphyrins on proteins and lipids. Semin Hematol. 1989;26:105–113.
   PubMed Web of Science ®Google Scholar
• Ajioka RS, Phillips JD, Kushner JP. Biosynthesis of heme in mammals. Biochim Biophys Acta. 2006;1763:723–736.
   PubMed Web of Science ®Google Scholar
• Khan AA, Quigley JG. Control of intracellular heme levels: heme transporters and heme oxygenases. Biochim Biophys Acta. 2011;1813:668–682.
   PubMed Web of Science ®Google Scholar
• Padmanaban G, Rangarajan PN. Heme metabolism of plasmodium is a major antimalarial target. Biochem Biophys Res Commun. 2000;268:665–668.
   PubMed Web of Science ®Google Scholar
• Huynh C, Yuan X, Miguel DC, et al. Heme uptake by Leishmania amazonensis is mediated by the transmembrane protein LHR1. PLoS Pathog. 2012;8:e1002795.
   PubMed Web of Science ®Google Scholar
• Miguel DC, Flannery AR, Mittra B, et al. Heme uptake mediated by lhr1 is essential for Leishmania amazonensis virulence. Infect Immun. 2013;81:3620–3626.
   PubMed Web of Science ®Google Scholar
• Nielsen MJ, Moestrup SK. Receptor targeting of hemoglobin mediated by the haptoglobins: roles beyond heme scavenging. Blood. 2009;114:764–771.
   PubMed Web of Science ®Google Scholar
• Vanhollebeke B, De Muylder G, Nielsen MJ, et al. A haptoglobin-hemoglobin receptor conveys innate immunity to Trypanosoma brucei in humans. Science. 2008;320:677–681.
   PubMed Web of Science ®Google Scholar
• Bishop JR, Shimamura M, Hajduk SL. Insight into the mechanism of trypanosome lytic factor-1 killing of Trypanosoma brucei brucei. Mol Biochem Parasitol. 2001;118:33–40.
   PubMed Web of Science ®Google Scholar
• Uzureau P, Uzureau S, Lecordier L, et al. Mechanism of Trypanosoma brucei gambiense resistance to human serum. Nature. 2013;501:430–434.
   PubMed Web of Science ®Google Scholar
• Dauchy F-A, Bonhivers M, Landrein N, et al. Trypanosoma brucei CYP51: essentiality and targeting therapy in an experimental model. PLoS Negl Trop Dis. 2016;10:e0005125.
   PubMed Web of Science ®Google Scholar
• Krishnamurthy P, Xie T, Schuetz JD. The role of transporters in cellular heme and porphyrin homeostasis. Pharmacol Ther. 2007;114:345–358.
   PubMed Web of Science ®Google Scholar
• Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum Genomics. 2009;3:281–290.
   PubMedGoogle Scholar
• Campos-Salinas J, Cabello-Donayre M, García-Hernández R, et al. A new ATP-binding cassette protein is involved in intracellular haem trafficking in Leishmania. Mol Microbiol. 2011;79:1430–1444.
   PubMed Web of Science ®Google Scholar
• Martínez-García M, Campos-Salinas J, Cabello-Donayre M, et al. LmABCB3, an atypical mitochondrial ABC transporter essential for Leishmania major virulence, acts in heme and cytosolic iron/sulfur clusters biogenesis. Parasit Vectors. 2016;9:7.
   PubMed Web of Science ®Google Scholar
• Cabello-Donayre M, Malagarie-Cazenave S, Campos-Salinas J, et al. Trypanosomatid parasites rescue heme from endocytosed hemoglobin through lysosomal HRG transporters. Mol Microbiol. 2016;101:895–908.
   PubMed Web of Science ®Google Scholar
• Cupello MP, Souza CF, Buchensky C, et al. The heme uptake process in Trypanosoma cruzi epimastigotes is inhibited by heme analogues and by inhibitors of ABC transporters. Acta Trop. 2011;120:211–218.
   PubMed Web of Science ®Google Scholar
• Merli ML, Pagura L, Hernández J, et al. The Trypanosoma cruzi protein TcHTE is critical for heme uptake. PLoS Negl Trop Dis. 2016;10:e0004359.
   PubMed Web of Science ®Google Scholar
• Owens CP, Chim N, Goulding CW. Insights on how the Mycobacterium tuberculosis heme uptake pathway can be used as a drug target. Future Med Chem. 2013;5:1391–1403.
   PubMed Web of Science ®Google Scholar
• Warren MJ. In black and white the colours of life—an introduction to the chemistry of porphyrins and related compounds. Trends Biochem Sci. 1997;22:409–410.
   Google Scholar
• Vanderesse R, Colombeau L, Frochot C, et al. Inactivation of malaria parasites in blood: PDT vs inhibition of hemozoin formation. In: Rodriguez-Morales AJ, editor. Current topics in malaria. Rijeka: InTech; 2016. p. 217–221.
   Google Scholar
• Cole KA, Ziegler J, Evans CA, et al. Metalloporphyrins inhibit beta-hematin (hemozoin) formation. J Inorg Biochem. 2000;78:109–115.
   PubMed Web of Science ®Google Scholar
• Begum K, Kim H-S, Kumar V, et al. In vitro antimalarial activity of metalloporphyrins against Plasmodium falciparum. Parasitol Res. 2003;90:221–224.
   PubMed Web of Science ®Google Scholar
• Abada Z, Cojean S, Pomel S, et al. Synthesis and antiprotozoal activity of original porphyrin precursors and derivatives. Eur J Med Chem. 2013;67:158–165.
   PubMed Web of Science ®Google Scholar
• Alves E, Iglesias BA, Deda DK, et al. Encapsulation of metalloporphyrins improves their capacity to block the viability of the human malaria parasite Plasmodium falciparum. Nanomedicine. 2015;11:351–358.
   PubMed Web of Science ®Google Scholar
• Nyarko E, Hara T, Grab DJ, et al. In vitro toxicity of palladium(II) and gold(III) porphyrins and their aqueous metal ion counterparts on Trypanosoma brucei brucei growth. Chem Biol Interact. 2004;148:19–25.
   PubMed Web of Science ®Google Scholar
• Gomes ML, DeFreitas-Silva G, dos Reis PG, et al. Synthesis and characterization of bismuth(III) and antimony(V) porphyrins: high antileishmanial activity against antimony-resistant parasite. J Biol Inorg Chem. 2015;20:771–779.
   PubMed Web of Science ®Google Scholar
• Fan W, Huang P, Chen X. Overcoming the Achilles' heel of photodynamic therapy. Chem Soc Rev. 2016;45:6488–6519.
   PubMed Web of Science ®Google Scholar
• Juarranz Á, Jaén P, Sanz-Rodríguez F, et al. Photodynamic therapy of cancer. Basic principles and applications. Clin Transl Oncol. 2008;10:148–154.
   PubMed Web of Science ®Google Scholar
• Fukuda H, Casas A, Chueke F, et al. Photodynamic action of endogenously synthesized porphyrins from aminolevulinic acid, using a new model for assaying the effectiveness of tumoral cell killing. Int J Biochem. 1993;25:1395–1398.
   PubMedGoogle Scholar
• Robertson CA, Evans DH, Abrahamse H. Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT. J Photochem Photobiol B. 2009;96:1–8.
   PubMed Web of Science ®Google Scholar
• Hryhorenko EA, Oseroff AR, Morgan J, et al. Antigen specific and nonspecific modulation of the immune response by aminolevulinic acid based photodynamic therapy. Immunopharmacology. 1998;40:231–240.
   PubMedGoogle Scholar
• Baptista MS, Wainwright M. Photodynamic antimicrobial chemotherapy (PACT) for the treatment of malaria, leishmaniasis and trypanosomiasis. Braz J Med Biol Res. 2011;44:1–10.
   PubMed Web of Science ®Google Scholar
• Szeimies R-M, Morton CA, Sidoroff A, et al. Photodynamic therapy for non-melanoma skin cancer. Acta Derm Venereol. 2005;85:483–490.
   PubMed Web of Science ®Google Scholar
• Davids LM, Kleemann B. Combating melanoma: the use of photodynamic therapy as a novel, adjuvant therapeutic tool. Cancer Treat Rev. 2011;37:465–475.
   PubMed Web of Science ®Google Scholar
• Simone CB, Cengel KA. Photodynamic therapy for lung cancer and malignant pleural mesothelioma. Semin Oncol. 2014;41:820–830.
   PubMed Web of Science ®Google Scholar
• Kawczyk-Krupka A, Bugaj AM, Latos W, et al. Photodynamic therapy in colorectal cancer treatment- the state of the art in clinical trials. Photodiagnosis Photodyn Ther. 2015;12:545–553.
   PubMed Web of Science ®Google Scholar
• Shimao H, Hiki Y. Photodynamic therapy for esophageal cancer. Gan to Kagaku Ryoho. 1996;23:36–40.
   PubMedGoogle Scholar
• Uzdensky AB, Berezhnaya E, Kovaleva V, et al. Photodynamic therapy: a review of applications in neurooncology and neuropathology. J Biomed Opt. 2015;20:61108.
   PubMed Web of Science ®Google Scholar
• Kharkwal GB, Sharma SK, Huang YY, et al. Photodynamic therapy for infections: clinical applications. Lasers Surg Med. 2011;43:755–767.
   PubMed Web of Science ®Google Scholar
• Lyon JP, Moreira LM, PCG d. M, et al. Photodynamic therapy for pathogenic fungi. Mycoses. 2011;54:e265–e271.
   PubMed Web of Science ®Google Scholar
• Gardlo K, Horska Z, Enk CD, et al. Treatment of cutaneous leishmaniasis by photodynamic therapy. J Am Acad Dermatol. 2003;48:893–896.
   PubMed Web of Science ®Google Scholar
• Van Der Snoek EM, Robinson DJ, Van Hellemond JJ, et al. A review of photodynamic therapy in cutaneous leishmaniasis. J Eur Acad Dermatol Venereol. 2008;22:918–922.
   PubMed Web of Science ®Google Scholar
• Asilian A, Davami M. Comparison between the efficacy of photodynamic therapy and topical paromomycin in the treatment of Old World cutaneous leishmaniasis: a placebo-controlled, randomized clinical trial. Clin Exp Dermatol. 2006;31:634–637.
   PubMed Web of Science ®Google Scholar
• Sohl S, Kauer F, Paasch U, et al. Photodynamic treatment of cutaneous leishmaniasis. J Dtsch Dermatol Ges. 2007;5:128–130.
   PubMedGoogle Scholar
• Enk CD, Nasereddin A, Alper R, et al. Br J Dermatol. 2015;172:1364–1370.
   PubMed Web of Science ®Google Scholar
• Mateus JE, Valdivieso W, Hernández IP, et al. Cell accumulation and antileishmanial effect of exogenous and endogenous protoporphyrin IX after photodynamic treatment. Biomedica. 2014;34:589–597.
   PubMed Web of Science ®Google Scholar
• Kosaka S, Akilov OE, O'Riordan K, et al. A mechanistic study of δ-aminolevulinic acid-based photodynamic therapy for cutaneous leishmaniasis. J Invest Dermatol. 2007;127:1546–1549.
   PubMed Web of Science ®Google Scholar
• Rose AL, Waite TD. Chemiluminescence of luminol in the presence of iron(II) and oxygen: oxidation mechanism and implications for its analytical use. Anal Chem. 2001;73:5909–5920.
   PubMed Web of Science ®Google Scholar
• Sigala PA, Crowley JR, Henderson JP, et al. Deconvoluting heme biosynthesis to target blood-stage malaria parasites. Elife. 2015;4:e09143.
   Web of Science ®Google Scholar
• Peloi LS, Biondo CEG, Kimura E, et al. Photodynamic therapy for American cutaneous leishmaniasis: the efficacy of methylene blue in hamsters experimentally infected with Leishmania (Leishmania) amazonensis. Exp Parasitol. 2011;128:353–356.
   PubMed Web of Science ®Google Scholar
• Sbeghen MR, Voltarelli EM, Campois TG, et al. Topical and intradermal efficacy of photodynamic therapy with methylene blue and light-emitting diode in the treatment of cutaneous leishmaniasis caused by Leishmania braziliensis. J Lasers Med Sci. 2015;6:106–111.
   PubMed Web of Science ®Google Scholar
• Wendel S. Transfusion transmitted Chagas disease: is it really under control?. Acta Trop. 2010;115:28–34.
   PubMed Web of Science ®Google Scholar
• Gironés N, Bueno JL, Carrión J, et al. The efficacy of photochemical treatment with methylene blue and light for the reduction of Trypanosoma cruzi in infected plasma. Vox Sang. 2006;91:285–291.
   PubMed Web of Science ®Google Scholar
• Kalkanidis M, Klonis N, Tilley L, et al. Novel phenothiazine antimalarials: synthesis, antimalarial activity, and inhibition of the formation of beta-haematin. Biochem Pharmacol. 2002;63:833–842.
   PubMed Web of Science ®Google Scholar
• Schirmer RH, Coulibaly B, Stich A, et al. Methylene blue as an antimalarial agent. Redox Rep. 2003;8:272–275.
   PubMed Web of Science ®Google Scholar
• Bawa S, Kumar S, Drabu S, et al. Structural modifications of quinoline-based antimalarial agents: recent developments. J Pharm Bioall Sci. 2010;2:64–71.
   PubMedGoogle Scholar
• O’Neill PM, Barton VE, Ward SA, et al. 4-Aminoquinolines: chloroquine, amodiaquine and next-generation analogues. Milestones Drug Ther. 2012;41:19–44.
   Google Scholar
• Egan TJ. Structure-function relationships in chloroquine and related 4-aminoquinoline antimalarials. Mini Rev Med Chem. 2001;1:113–123.
   PubMedGoogle Scholar
• Burgess SJ, Kelly JX, Shomloo S, et al. Synthesis, structure-activity relationship, and mode-of-action studies of antimalarial reversed chloroquine compounds. J Med Chem. 2010;53:6477–6489.
   PubMed Web of Science ®Google Scholar
• Singh K, Kaur H, Smith P, et al. Quinoline-pyrimidine hybrids: synthesis, antiplasmodial activity, SAR, and mode of action studies. J Med Chem. 2014;57:435–448.
   PubMed Web of Science ®Google Scholar
• Kumar S, Bandyopadhyay U. Free heme toxicity and its detoxification systems in human. Toxicol Lett. 2005;157:175–188.
   PubMed Web of Science ®Google Scholar
• Coronado LM, Nadovich CT, Spadafora C. Malarial hemozoin: from target to tool. Biochim Biophys Acta Gen Subj. 2014;1840:2032–2041.
   PubMed Web of Science ®Google Scholar
• Egan TJ. Interactions of quinoline antimalarials with hematin in solution. J Inorg Biochem. 2006;100:916–926.
   PubMed Web of Science ®Google Scholar
• Sander T, Freyss J, Von Korff M, et al. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J Chem Inf Model. 2015;55:460–473.
   PubMed Web of Science ®Google Scholar
• Combrinck JM, Mabotha TE, Ncokazi KK, et al. Insights into the role of heme in the mechanism of action of antimalarials. ACS Chem Biol. 2013;8:133–137.
   PubMed Web of Science ®Google Scholar
• Foley M, Tilley L. Quinoline antimalarials: mechanisms of action and resistance and prospects for new agents. Pharmacol Ther. 1998;79:55–87.
   PubMed Web of Science ®Google Scholar
• Lechuga GC, Borges JC, Calvet CM, et al. Interactions between 4-aminoquinoline and heme: promising mechanism against Trypanosoma cruzi. Int J Parasitol Drugs Drug Resist. 2016;6:154–164.
   PubMed Web of Science ®Google Scholar
• Huy NT, Kamei K, Kondo Y, et al. Effect of antifungal azoles on the heme detoxification system of malarial parasite. J Biochem. 2002;131:437–444.
   PubMed Web of Science ®Google Scholar
• Tiffert T, Ginsburg H, Krugliak M, et al. Potent antimalarial activity of clotrimazole in in vitro cultures of Plasmodium falciparum. Proc Natl Acad Sci USA. 2000;97:331–336.
   PubMed Web of Science ®Google Scholar
• Huy NT, Takano R, Hara S, et al. Enhancement of heme-induced membrane damage by the anti-malarial clotrimazole: the role of colloid-osmotic forces. Biol Pharm Bull. 2004;27:361–365.
   PubMed Web of Science ®Google Scholar
• Ignatushchenko MV, Winter RW, Bächinger HP, et al. Xanthones as antimalarial agents; studies of a possible mode of action. FEBS Lett. 1997;409:67–73.
   PubMed Web of Science ®Google Scholar
• Ignatushchenko MV, Winter RW, Riscoe M. Xanthones as antimalarial agents: stage specificity. Am J Trop Med Hyg. 2000;62:77–81.
   PubMed Web of Science ®Google Scholar
• Riscoe M, Kelly JX, Winter R. Xanthones as antimalarial agents: discovery, mode of action, and optimization. Curr Med Chem. 2005;12:2539–2549.
   PubMed Web of Science ®Google Scholar
• Kelly JX, Winter R, Peyton DH, et al. Optimization of xanthones for antimalarial activity: the 3,6-bis-omega-diethylaminoalkoxyxanthone series. Antimicrob Agents Chemother. 2002;46:144–150.
   PubMed Web of Science ®Google Scholar
• Kelly JX, Ignatushchenko MV, Bouwer HG, et al. Antileishmanial drug development: exploitation of parasite heme dependency. Mol Biochem Parasitol. 2003;126:43–49.
   PubMed Web of Science ®Google Scholar
• Kelly JX, Winter RW, Cornea A, et al. The kinetics of uptake and accumulation of 3,6-bis-omega-diethylamino-amyloxyxanthone by the human malaria parasite Plasmodium falciparum. Mol Biochem Parasitol. 2002;123:47–54.
   PubMed Web of Science ®Google Scholar
• World Health Organization. Guidelines for the treatment of malaria. 2nd ed. Geneva, Switzerland: WHO; 2010.
   Google Scholar
• Klayman DL. Qinghaosu (artemisinin): an antimalarial drug from China. Science. 1985;228:1049–1055.
   PubMed Web of Science ®Google Scholar
• Pandey N, Pandey-Rai S. Updates on artemisinin: an insight to mode of actions and strategies for enhanced global production. Protoplasma. 2016;253:15–30.
   PubMed Web of Science ®Google Scholar
• O'Neill PM, Barton VE, Ward SA. The molecular mechanism of action of artemisinin-the debate continues. Molecules. 2010;15:1705–1721.
   PubMed Web of Science ®Google Scholar
• Zhang S, Gerhard GS. Heme activates artemisinin more efficiently than hemin, inorganic iron, or hemoglobin. Bioorg Med Chem. 2008;16:7853–7861.
   PubMed Web of Science ®Google Scholar
• Klonis N, Crespo-Ortiz MP, Bottova I, et al. Artemisinin activity against Plasmodium falciparum requires hemoglobin uptake and digestion. Proc Natl Acad Sci USA. 2011;108:11405–11410.
   PubMed Web of Science ®Google Scholar
• Sen R, Ganguly S, Saha P, et al. Efficacy of artemisinin in experimental visceral leishmaniasis. Int J Antimicrob Agents. 2010;36:43–49.
   PubMed Web of Science ®Google Scholar
• D'Angelo JG, Bordón C, Posner GH, et al. Artemisinin derivatives inhibit Toxoplasma gondii in vitro at multiple steps in the lytic cycle. J Antimicrob Chemother. 2009;63:146–150.
   PubMed Web of Science ®Google Scholar
• Mishina YV, Krishna S, Haynes RK, et al. Artemisinins inhibit Trypanosoma cruzi and Trypanosoma brucei rhodesiense in vitro growth. Antimicrob Agents Chemother. 2007;51:1852–1854.
   PubMed Web of Science ®Google Scholar
• Rodriguez M, Claparols C, Robert A, et al. Alkylation of microperoxidase-11 by the antimalarial drug artemisinin. Chembiochem. 2002;3:1147–1149.
   PubMed Web of Science ®Google Scholar
• Kannan R, Sahal D, Chauhan VS. Heme-artemisinin adducts are crucial mediators of the ability of artemisinin to inhibit heme polymerization. Chem Biol. 2002;9:321–332.
   PubMed Web of Science ®Google Scholar
• Loup C, Lelièvre J, Benoit-Vical F, et al. Trioxaquines and heme-artemisinin adducts inhibit the in vitro formation of hemozoin better than chloroquine. Antimicrob Agents Chemother. 2007;51:3768–3770.
   PubMed Web of Science ®Google Scholar
• Kannan R, Kumar K, Sahal D, et al. Reaction of artemisinin with haemoglobin: implications for antimalarial activity. Biochem J. 2005;385:409–418.
   PubMed Web of Science ®Google Scholar
• Robert A, Benoit-Vical F, Claparols C, et al. The antimalarial drug artemisinin alkylates heme in infected mice. Proc Natl Acad Sci USA. 2005;102:13676–13680.
   PubMed Web of Science ®Google Scholar
• Selmeczi K, Robert A, Claparols C, et al. Alkylation of human hemoglobin A0 by the antimalarial drug artemisinin. FEBS Lett. 2004;556:245–248.
   PubMed Web of Science ®Google Scholar
• Yang YZ, Little B, Meshnick SR. Alkylation of proteins by artemisinin. Effects of heme, pH, and drug structure. Biochem Pharmacol. 1994;48:569–573.
   PubMed Web of Science ®Google Scholar
• Eichhorn T, Winter D, Büchele B, et al. Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum. Biochem Pharmacol. 2013;85:38–45.
   PubMed Web of Science ®Google Scholar
• Bhisutthibhan J, Pan XQ, Hossler PA, et al. The Plasmodium falciparum translationally controlled tumor protein homolog and its reaction with the antimalarial drug artemisinin. J. Biol. Chem. 1998;273:16192–16198.
   PubMed Web of Science ®Google Scholar
• Lucas AT, Fu X, Liu J, et al. Ligand binding reveals a role for heme in translationally-controlled tumor protein dimerization. PLoS One. 2014;9:1–17.
   Web of Science ®Google Scholar
• Eckstein-Ludwig U, Webb RJ, Van Goethem IDA, et al. Artemisinins target the SERCA of Plasmodium falciparum. Nature. 2003;424:957–961.
   PubMed Web of Science ®Google Scholar
• Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: a major update to the DrugBank database for 2018. Nucleic Acids Res. 2018;46:D1074–D1082.
   PubMed Web of Science ®Google Scholar
• Li X, Wang X, Zhao K, et al. A novel approach for identifying the heme-binding proteins from mouse tissues. Genomics Proteomics Bioinformatics. 2003;1:78–86.
   PubMedGoogle Scholar
• Wang J, Zhang CJ, Chia WN, et al. Haem-activated promiscuous targeting of artemisinin in Plasmodium falciparum. Nat Commun. 2015;6:10111.
   PubMed Web of Science ®Google Scholar
• Ravindra KC, Ho WE, Cheng C, et al. Untargeted proteomics and systems-based mechanistic investigation of artesunate in human bronchial epithelial cells. Chem Res Toxicol. 2015;28:1903–1913.
   PubMed Web of Science ®Google Scholar
• Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA. 1968;61:748–755.
   PubMed Web of Science ®Google Scholar
• Chung SW, Hall SR, Perrella MA. Role of haem oxygenase-1 in microbial host defence. Cell Microbiol. 2009;11:199–207.
   PubMed Web of Science ®Google Scholar
• Wagener FA, Volk HD, Willis D, et al. Different faces of the heme-heme oxygenase system in inflammation. Pharmacol Rev. 2003;55:551–571.
   PubMed Web of Science ®Google Scholar
• Paiva CN, Feijó DF, Dutra FF, et al. Oxidative stress fuels Trypanosoma cruzi infection in mice. J Clin Invest. 2012;122:2531–2542.
   PubMed Web of Science ®Google Scholar
• Gutierrez FR, Pavanelli WR, Medina TS, et al. Haeme oxygenase activity protects the host against excessive cardiac inflammation during experimental Trypanosoma cruzi infection. Microbes Infect. 2014;16:28–39.
   PubMed Web of Science ®Google Scholar
• Ferrándiz ML, Devesa I. Inducers of heme oxygenase-1. Curr Pharm Des. 2008;14:473–486.
   PubMed Web of Science ®Google Scholar
• Koide T, Nose M, Ogihara Y, et al. Leishmanicidal effect of curcumin in vitro. Biol Pharm Bull. 2002;25:131–133.
   PubMed Web of Science ®Google Scholar
• Reddy RC, Vatsala PG, Keshamouni VG, et al. Curcumin for malaria therapy. Biochem Biophys Res Commun. 2005;326:472–474.
   PubMed Web of Science ®Google Scholar
• Nagajyothi F, Zhao D, Weiss LM, et al. Curcumin treatment provides protection against Trypanosoma cruzi infection. Parasitol Res. 2012;110:2491–2499.
   PubMed Web of Science ®Google Scholar
• Novaes RD, Sartini MVP, Rodrigues JPF, et al. Curcumin enhances the anti-Trypanosoma cruzi activity of benznidazole-based chemotherapy in acute experimental Chagas disease. Antimicrob Agents Chemother. 2016;60:3355–3364.
   PubMed Web of Science ®Google Scholar
• Wang N-P, Wang Z-F, Tootle S, et al. Curcumin promotes cardiac repair and ameliorates cardiac dysfunction following myocardial infarction. Br J Pharmacol. 2012;167:1550–1562.
   PubMed Web of Science ®Google Scholar
• Rimbaud S, Ruiz M, Piquereau J, et al. Resveratrol improves survival, hemodynamics and energetics in a rat model of hypertension leading to heart failure. PLoS One. 2011;6:e26391.
   PubMed Web of Science ®Google Scholar
• Frémont L. Biological effects of resveratrol. Antioxid Redox Signal. 2001;3:1041–1064.
   PubMed Web of Science ®Google Scholar
• Cheng TH, Liu JC, Lin H, et al. Inhibitory effect of resveratrol on angiotensin II-induced cardiomyocyte hypertrophy. Naunyn Schmiedebergs Arch Pharmacol. 2004;369:239–244.
   PubMed Web of Science ®Google Scholar
• Vilar-Pereira G, Carneiro VC, Mata-Santos H, et al. Resveratrol reverses functional Chagas heart disease in mice. PLoS Pathog. 2016;12:e1005947.
   PubMed Web of Science ®Google Scholar
• Pham NK, Mouriz J, Kima PE. Leishmania pifanoi amastigotes avoid macrophage production of superoxide by inducing heme degradation. Infect Immun. 2005;73:8322–8333.
   PubMed Web of Science ®Google Scholar
• Luz NF, Andrade BB, Feijó DF, et al. Heme oxygenase-1 promotes the persistence of Leishmania chagasi infection. J Immunol. 2012;188:4460–4467.
   PubMed Web of Science ®Google Scholar
• Dorlo TPC, Balasegaram M, Beijnen JH, et al. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012;67:2576–2597.
   PubMed Web of Science ®Google Scholar
• Das S, Pandey K, Rabidas VN, et al. Effectiveness of miltefosine treatment in targeting anti-leishmanial HO-1/Nrf-2-mediated oxidative responses in visceral leishmaniasis patients. J Antimicrob Chemother. 2013;68:2059–2065.
   PubMed Web of Science ®Google Scholar
• Ferreira A, Balla J, Jeney V, et al. A central role for free heme in the pathogenesis of severe malaria: the missing link? J Mol Med. 2008;86:1097–1111.
   PubMed Web of Science ®Google Scholar
• Seixas E, Gozzelino R, Chora A, et al. Heme oxygenase-1 affords protection against noncerebral forms of severe malaria. Proc Natl Acad Sci USA. 2009;106:15837–15842.
   PubMed Web of Science ®Google Scholar
• Pena AC, Penacho N, Mancio-Silva L, et al. A novel carbon monoxide-releasing molecule fully protects mice from severe malaria. Antimicrob Agents Chemother. 2012;56:1281–1290.
   PubMed Web of Science ®Google Scholar
• Okada K. The novel heme oxygenase-like protein from Plasmodium falciparum converts heme to bilirubin IXα in the apicoplast. FEBS Lett. 2009;583:313–319.
   PubMed Web of Science ®Google Scholar
• Sigala PA, Crowley JR, Hsieh S, et al. Direct tests of enzymatic heme degradation by the malaria parasite Plasmodium falciparum. J Biol Chem. 2012;287:37793–37807.
   PubMed Web of Science ®Google Scholar
• Cupello MP, Souza CF, Menna-Barreto RF, et al. Trypanosomatid essential metabolic pathway: new approaches about heme fate in Trypanosoma cruzi. Biochem Biophys Res Commun. 2014;449:216–221.
   PubMed Web of Science ®Google Scholar
• Lin YW, Wang J. Structure and function of heme proteins in non-native states: a mini-review. J Inorg Biochem. 2013;129:162–171.
   PubMed Web of Science ®Google Scholar
• Li T, Bonkovsky HL, Guo J. Structural analysis of heme proteins: implications for design and prediction. BMC Struct Biol. 2011;11:13.
   PubMed Web of Science ®Google Scholar
• Mansuri R, Kumar A, Rana S, et al. In vitro evaluation of antileishmanial activity of computationally screened compounds against ascorbate peroxidase to combat amphotericin B drug resistance. Antimicrob Agents Chemother. 2017;61:pii:e02429-16
   Web of Science ®Google Scholar
• Lepesheva GI, Hargrove TY, Anderson S, et al. Structural insights into inhibition of sterol 14α-demethylase in the human pathogen Trypanosoma cruzi. J Biol Chem. 2010;285:25582–25590.
   PubMed Web of Science ®Google Scholar
• Calvet CM, Vieira DF, Choi JY, et al. 4-Aminopyridyl-based CYP51 inhibitors as anti-Trypanosoma cruzi drug leads with improved pharmacokinetic profile and in vivo potency. J Med Chem. 2014;57:6989–7005.
   PubMed Web of Science ®Google Scholar
• Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera—a visualization system for exploratory research and analysis. J Comput Chem. 2004;25:1605–1612.
   PubMed Web of Science ®Google Scholar
• Fischer RT, Stam SH, Johnson PR, et al. Mechanistic studies of lanosterol 14 alpha-methyl demethylase: substrate requirements for the component reactions catalyzed by a single cytochrome P-450 isozyme. J Lipid Res. 1989;30:1621–1632.
   PubMed Web of Science ®Google Scholar
• Vieira DF, Choi JY, Calvet CM, et al. Binding mode and potency of N-indolyloxopyridinyl-4-aminopropanyl-based inhibitors targeting Trypanosoma cruzi CYP51. J Med Chem. 2014;57:10162–10175.
   PubMed Web of Science ®Google Scholar
• Lepesheva GI, Waterman MR. Sterol 14alpha-demethylase (CYP51) as a therapeutic target for human trypanosomiasis and leishmaniasis. Curr Top Med Chem. 2011;11:2060–2071.
   PubMed Web of Science ®Google Scholar
• Zvulunov A, Klaus S, Vardy D. Fluconazole for the treatment of cutaneous leishmaniasis. N Engl J Med. 2002;347:370–371.
   PubMed Web of Science ®Google Scholar
• Weinrauch L, Livshin R, Even-Paz Z, et al. Efficacy of ketoconazole in cutaneous leishmaniasis. Arch Dermatol Res. 1983;275:353–354.
   PubMed Web of Science ®Google Scholar
• Urbina JA, Payares G, Contreras LM, et al. Antiproliferative effects and mechanism of action of SCH 56592 against Trypanosoma (Schizotrypanum) cruzi: in vitro and in vivo studies. Antimicrob Agents Chemother. 1998;42:1771–1777.
   PubMed Web of Science ®Google Scholar
• Molina J, Martins-Filho O, Brener Z, et al. Activities of the triazole derivative SCH 56592 (Posaconazole) against drug-resistant strains of the protozoan parasite Trypanosoma (Schizotrypanum) cruzi in immunocompetent and immunosuppressed murine hosts. Antimicrob Agents Chemother. 2000;44:150–155.
   PubMed Web of Science ®Google Scholar
• Hargrove TY, Wawrzak Z, Alexander PW, et al. Complexes of Trypanosoma cruzi sterol 14α-demethylase (CYP51) with two pyridine-based drug candidates for Chagas disease: structural basis for pathogen selectivity. J Biol Chem. 2013;288:31602–31615.
   PubMed Web of Science ®Google Scholar
• Buckner FS, Urbina JA. Recent developments in sterol 14-demethylase inhibitors for Chagas disease. Int J Parasitol Drugs Drug Resist. 2012;2:236–242.
   PubMed Web of Science ®Google Scholar
• 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;370:1899–1908.
   PubMed Web of Science ®Google Scholar
• Lepesheva GI, Villalta F, Waterman MR. Targeting Trypanosoma cruzi sterol 14α-demethylase (CYP51). Adv Parasitol. 2011;75:65–87.
   PubMed Web of Science ®Google Scholar
• Villalta F, Dobish MC, Nde PN, et al. VNI cures acute and chronic experimental Chagas disease. J Infect Dis. 2013;208:504–511.
   PubMed Web of Science ®Google Scholar
• Doyle PS, Chen C-K, Johnston JB, et al. A nonazole CYP51 inhibitor cures Chagas’ disease in a mouse model of acute infection. Antimicrob Agents Chemother. 2010;54:2480–2488.
   PubMed Web of Science ®Google Scholar
• Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4’-chlorophenyl) cyclohexyl]-3-hydroxy-1,4-naphthoquinone (566C80). Biochem Pharmacol. 1992;43:1545–1553.
   PubMed Web of Science ®Google Scholar
• Srivastava IK, Rottenberg H, Vaidya AB. Atovaquone, a broad spectrum antiparasitic drug, collapses mitochondrial membrane potential in a malarial parasite. J Biol Chem. 1997;272:3961–3966.
   PubMed Web of Science ®Google Scholar
• Nixon GL, Moss DM, Shone AE, et al. Antimalarial pharmacology and therapeutics of atovaquone. J Antimicrob Chemother. 2013;68:977–985.
   PubMed Web of Science ®Google Scholar
• Poulos TL. Heme enzyme structure and function. Chem Rev. 2014;114:3919–3962.
   PubMed Web of Science ®Google Scholar
• Adak S, Datta AK. Leishmania major encodes an unusual peroxidase that is a close homologue of plant ascorbate peroxidase: a novel role of the transmembrane domain. Biochem J. 2005;390:465–474.
   PubMed Web of Science ®Google Scholar
• Dolai S, Yadav RK, Pal S, et al. Overexpression of mitochondrial Leishmania major ascorbate peroxidase enhances tolerance to oxidative stress-induced programmed cell death and protein damage. Eukaryot Cell. 2009;8:1721–1731.
   PubMedGoogle Scholar
• Pal S, Dolai S, Yadav RK, et al. Ascorbate peroxidase from Leishmania major controls the virulence of infective stage of promastigotes by regulating oxidative stress. PLoS One. 2010;5:e11271.
   PubMed Web of Science ®Google Scholar
• Wilkinson SR, Obado SO, Mauricio IL, et al. Trypanosoma cruzi expresses a plant-like ascorbate-dependent hemoperoxidase localized to the endoplasmic reticulum. Proc Natl Acad Sci USA. 2002;99:13453–13458.
   PubMed Web of Science ®Google Scholar
• Taylor MC, Lewis MD, Francisco AF, et al. The Trypanosoma cruzi vitamin C dependent peroxidase confers protection against oxidative stress but is not a determinant of virulence. PLoS Negl Trop Dis. 2015;99:13453–13458.
   Google Scholar
• Nogueira FB, Rodrigues JFA, Correa MMS, et al. The level of ascorbate peroxidase is enhanced in benznidazole-resistant populations of Trypanosoma cruzi and its expression is modulated by stress generated by hydrogen peroxide. Mem Inst Oswaldo Cruz. 2012;107:494–502.
   PubMed Web of Science ®Google Scholar
• Girvan HM, Munro AW. Heme sensor proteins. J Biol Chem. 2013;288:13194–13203.
   PubMed Web of Science ®Google Scholar