Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 117 | 2022
Perspective
Natural compounds based chemotherapeutic against Chagas disease and leishmaniasis: mitochondrion as a strategic target
Universidade Estadual de Maringá, Laboratório de Inovação Tecnológica no Desenvolvimento de Fármacos e Cosméticos, Maringá, PR, Brasil
DOI: 10.1590/0074-02760220396
ABSTRACT
Over the past years, natural products have been explored in order to find biological active substances to treat various diseases. Regarding their potential action against parasites such as trypanosomatids, specially Trypanosoma cruzi and Leishmania spp., much advance has been achieved. Extracts and purified molecules of several species from genera Piper, Tanacetum, Porophyllum, and Copaifera have been widely investigated by our research group and exhibited interesting antitrypanosomal and antileishmanial activities. These natural compounds affected different structures in parasites, and we believe that the mitochondrion is a strategic target to induce parasite death. Considering that these trypanosomatids have a unique mitochondrion, this cellular target has been extensively studied aiming to find more selective drugs, since the current treatment of these neglected tropical diseases has some challenges such as high toxicity and prolonged treatment time. Here, we summarise some results obtained with natural products from our research group and we further highlighted some strategies that must be considered to finally develop an effective chemotherapeutic agent against these parasites.
REFERENCES
01. WHO - World Health Organization. Working to overcome the global impact of neglected tropical diseases: first WHO report on neglected tropical diseases. 2010. Available from: https://apps. who.int/iris/handle/10665/44440.
02. Alviano D, Barreto AL, Dias F, Rodrigues I, Rosa M, Alviano C, et al. Conventional therapy and promising plant-derived compounds against trypanosomatid parasites. Front Microbiol. 2012; 3(283): 1-10.
03. WHO - World Health Organization. Chagas disease (American trypanosomiasis). 2020. Available from: https://www.who.int/ news-room/fact-sheets/detail/chagas-disease.
04. Villalta F, Rachakonda G. Advances in preclinical approaches to Chagas disease drug discovery. Expert Opin. 2019; 14(11): 1161-74.
05. Karagiannis-Voules DA, Scholte RGC, Guimarães LH, Utzinger J, Vounatsou P. Bayesian geostatistical modeling of leishmaniasis incidence in Brazil. PLoS Negl Trop Dis. 2013; 7(5): e2213.
06. WHO - World Health Organization. Leishmaniasis. 2020. Available from: https://www.who .int/leishmaniasis/en/.
07. Chagas C. Nova tripanozomiase humana. Estudos sobre a morfolojia e o ciclo evolutivo do Schizotrypanum cruzi n. gen., n. sp., ajente etiolojico de nova entidade morbida do homem. Mem Inst Oswaldo Cruz. 1909; 1(2): 159-218.
08. Coura JR. Present situation and new strategies for Chagas disease chemotherapy - a proposal. Mem Inst Oswaldo Cruz. 2009; 104(4): 549-54.
09. De Menezes JP, Guedes CE, Petersen AL, Fraga DB, Veras PS. Advances in development of new treatment for leishmaniasis. Biomed Res Int. 2015; 2015: 815023.
10. Saleem M, Nazir M, Ali MS, Hussain H, Lee YS, Riaza N, et al. Antimicrobial natural products: an update on future antibiotic drug candidates. Nat Prod Rep. 2010; 27: 238-54.
11. Hoet S, Opperdoes F, Brun R, Quetin-Leclercq J. Natural products active against African trypanosomes: a step towards new drugs. Nat Prod Rep. 2004; 21: 353-64.
12. Copp BR, Pearce A. Natural product growth inhibitors of Mycobacterium tuberculosis. Nat Prod Rep. 2007; 24: 278-97.
13. Kuo RY, Qian K, Morris-Natschke SL, Lee KH. Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents. Nat Prod Rep. 2009; 26: 1321-44.
14. Magadula JJ, Erasto P. Bioactive natural products derived from the East African flora. Nat Prod Rep. 2009; 26: 1535-54.
15. Cowan MM. Plant products as antimicrobial agents. Clin Microbiol Rev. 1999; 12: 564-82.
16. Alviano DS, Alviano CS. Plant extracts: search for new alternatives to treat microbial diseases. Curr Pharm Biotechnol. 2009; 10: 106-21.
17. Izumi E, Ueda-Nakamura T, Dias-Filho BP, Veiga Jr VF, Nakamura CV. Natural products and Chagas’ disease: a review of plant compounds studies for activity against Trypanosoma cruzi. Nat Prod Rep. 2011; 28: 809-23.
18. Brady SF, Simmons L, Kima JH, Schmidt EW. Metagenomic approaches to natural products from free-living and symbiotic organisms. Nat Prod Rep. 2009; 26: 1488-503.
19. Blunt JW, Copp BR, Munro MHG, Northcote PT, Prinsep MR. Marine natural products. Nat Prod Rep. 2010; 27: 165-237.
20. Cunha Jr RM, Domingues PBA, Ambrósio RO, Martins CAF, Silva J, Pieri F. Brazilian Amazon plants: an overview of chemical composition and biological activity. Natural resources management and biological sciences. IntechOpen. 2020; 1-16.
21. Rodrigues JC, Godinho JL, De Souza W. Biology of human pathogenic trypanosomatids: epidemiology, lifecycle and ultrastructure. Subcell Biochem. 2014; 74: 1-42.
22. Fidalgo LM, Gille L. Mitochondria and trypanosomatids: targets and drugs. Pharm Res. 2011; 28(11): 2758-70.
23. Menna-Barreto RFS, De Castro SL. The double-edged sword in pathogenic trypanosomatids: the pivotal role of mitochondria in oxidative stress and bioenergetics. BioMed Res Int. 2014; 2014: 14 pp.
24. Chance B, Sies H, Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979; 59: 527-605.
25. Sipos I, Tretter L, Adam-Vizi V. The production of reactive oxygen species in intact isolated nerve terminals is independent of the mitochondrial membrane potential. Neurochem Res. 2003; 28: 1575-81.
26. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014; 24(10): R453-62.
27. Kirkinezos IG, Moraes CT. Reactive oxygen species and mitochondrial diseases. Cell Dev Biol. 2001; 12: 449-57.
28. Piñeyro M, Pizarro J, Lema F, Pritsch O, Cayota A, Bentley G, et al. Crystal structure of the tryparedoxin peroxidase from the human parasite Trypanosoma cruzi. J Struct Biol. 2005; 150: 11-22.
29. Krauth-Siegel RL, Comini MA. Redox control in trypanosomatids, parasitic protozoa with trypanothione-based thiol metabolism. Biochim Biophys Acta. 2008; 1780: 1236-48.
30. Ariyanayagam MR, Fairlamb AH. Ovothiol and trypanothione as antioxidants in trypanosomatids. Mol Biochem Parasitol. 2001; 115: 189-98.
31. Leroux AE, Krauth-Siegel RL. Thiol redox biology of trypanosomatids and potential targets for chemotherapy. Mol Biochem Parasitol. 2016; 206(1): 67-74.
32. Lazarin-Bidoia D, Desoti VC, Ueda-Nakamura T, Dias-Filho BP, Nakamura CV, Silva SO. Further evidence of the trypanocidal action of eupomatenoid-5: confirmation of involvement of reactive oxygen species and mitochondria owing to a reduction in trypanothione reductase activity. Free Radic Biol Med. 2013; 60: 17-28.
33. Lazarin-Bidoia D, Desoti VC, Martins SC, Ribeiro FM, Din ZU, Rodrigues-Filho E, et al. Dibenzylideneacetones are potent trypanocidal compounds that affect the Trypanosoma cruzi redox system. Antimicrob Agents Chemother. 2016; 60(2): 890-903.
34. Luize PS, Tiuman TS, Morello LG, Maza PK, Ueda-Nakamura T, Dias-Filho BP, et al. Effects of medicinal plant extracts on growth of Leishmania (L.) amazonensis and Trypanosoma cruzi. Braz J Pharm Sci. 2005; 41: 85-94.
35. Luize PS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Nakamura CV. Activity of neolignans isolated from Piper regnellii (MIQ.) C.DC. var. pallescens (C.DC.) Yunk against Trypanosoma cruzi. Biol Pharm Bull. 2006; 10: 2126-30.
36. Luize PS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Morgado- Diaz JA, De Souza W, et al. Ultrastructural alterations induced by the neolignan dihydrobenzofuranic eupomatenoid-5 on epimastigote and amastigote forms of Trypanosoma cruzi. Parasitol Res. 2006; 100: 31-7.
37. Pelizzaro-Rocha KJ, Veiga-Santos P, Lazarin-Bidoia D, Ueda- -Nakamura T, Dias-Filho BP, Ximenes VF, et al. Trypanocidal action of eupomatenoid-5 is related to mitochondrion dysfunction and oxidative damage in Trypanosoma cruzi. Microbes Infect. 2011; 13: 1018-24.
38. Vendrametto MC, Santos AOD, Nakamura CV, Dias-Filho BP, Cortez DAG, Ueda-Nakamura T. Evaluation of antileishmanial activity of eupomatenoid-5, a compound isolated from leaves of Piper regnellii var. pallescens. Parasitol Res. 2010; 59(2): 154-8.
39. Garcia FP, Lazarin-Bidoia D, Ueda-Nakamura T, Silva SO, Nakamura CV. Eupomatenoid-5 isolated from leaves of Piper regnellii induces apoptosis in Leishmania amazonensis. Evid Based Complement Alternat Med. 2013; 2013: 940531.
40. Izumi E, Morello LG, Ueda-Nakamura T, Yamada-Ogatta SF, Dias-Filho BP, Cortez DAG, et al. Trypanosoma cruzi: antiprotozoal activity of parthenolide obtained from Tanacetum parthenium (L.) Schultz Bip. (Asteraceae, Compositae) against epimastigote and amastigote forms. Exp Parasitol. 2008; 118(3): 324-30.
41. Pelizzaro-Rocha KJ, Tiuman TS, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Nakamura CV. Synergistic effects of parthenolide and benznidazole on Trypanosoma cruzi. Phytomedicine. 2010; 18(1): 36-9.
42. Cogo J, Caleare AO, Ueda-Nakamura T, Dias-Filho BP, Ferreira ICP, Nakamura CV. Trypanocidal activity of guaianolide obtained from Tanacetum parthenium (L.) Schultz-Bip. and its combinational effect with benznidazole. Phytomedicine. 2012; 20(1): 59-66.
43. Tiuman TS, Ueda-Nakamura T, Dias-Filho BP, Cortez DAG, Nakamura CV. Studies on the effectiveness of Tanacetum parthenium against Leishmania amazonensis. Acta Protozool. 2005; 44: 245-51.
44. Tiuman TS, Ueda-Nakamura T, Cortez DA, Dias-Filho BP, Morgado- Díaz JA, Souza W, et al. Antileishmanial activity of parthenolide, a sesquiterpene lactone isolated from Tanacetum parthenium. Antimicrob Agents Chemother. 2005; 49: 176-82.
45. Takahashi HT, Novello CR, Ueda-Nakamura T, Dias-Filho BP, Mello JCP, Nakamura CV. Thiophene derivatives with antileishmanial activity isolated from aerial parts of Porophyllum ruderale (Jacq.) Cass. Molecules. 2011; 16: 3469-78.
46. Takahashi HT, Britta EA, Longhini R, Ueda-Nakamura T, Mello JCP, Nakamura CV. Antileishmanial activity of 5-methyl- 2,2’:5’,2?-terthiophene isolated from Porophyllum ruderale is related to mitochondrial dysfunction in Leishmania amazonensis. Planta Med. 2013; 79(5): 330-3.
47. Miranda N, Gerola AP, Novello CR, Ueda-Nakamura T, Silva SO, Dias-Filho BP, et al. Pheophorbide A, a compound isolated from the leaves of Arrabidaea chica, induces photodynamic inactivation of Trypanosoma cruzi. Photodiagnosis Photodyn Ther. 2017; 19: 256-65.
48. Veiga VF, Patitucci ML, Pinto AC. Controle de autenticidade de óleos de copaíba comerciais por cromatografia gasosa de alta resolução. Quim Nova. 1997; 20(6): 612-5.
49. Veiga VF, Pinto AC. O gênero Copaifera L. Quim Nova. 2002; 25(2): 273-86.
50. Barbosa PCS, Wiedemann LSM, Medeiros RS, Sampaio PTB, Vieira G, Veiga-Junior VF. Phytochemical fingerprints of copaiba oils (Copaifera multijuga Hayne) determined by multivariate analysis. Chem. Biodiversity. 2013; 10(7): 1350-60.
51. Santos AO, Ueda-Nakamura T, Dias-Filho BP, Veiga-Junior VF, Pinto AC, Nakamura CV. Effect of Brazilian copaiba oils on Leishmania amazonensis. J Ethnopharmacol. 2008; 120(2): 204-8.
52. Santos AO, Ueda-Nakamura T, Dias-Filho BP, Veiga-Junior VF, Nakamura CV. Copaiba oil: an alternative to development of new drugs against leishmaniasis. Evid Based Complement Alternat Med. 2012; 2012: 898419.
53. Santos AO, Costa MA, Ueda-Nakamura T, Dias-Filho BP, Veiga- -Junior VF, Lima MMS, et al. Leishmania amazonensis: effects of oral treatment with copaiba oil in mice. Exp Parasitol. 2011; 129(2): 145-51.
54. dos Santos AO, Izumi E, Ueda-Nakamura T, Dias-Filho BP, Veiga- Júnior VF, Nakamura CV. Antileishmanial activity of diterpene acids in copaiba oil. Mem Inst Oswaldo Cruz. 2013; 108(1): 59-64.
55. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Pinto AC, Nakamura CV. Terpenes from Copaifera demonstrated in vitro antiparasitic and synergic activity. J Med Chem. 2012; 55(7): 2994-3001.
56. Izumi E, Ueda-Nakamura T, Veiga-Júnior VF, Nakamura CV. Toxicity of oleoresins from the genus Copaifera in Trypanosoma cruzi: a comparative study. Planta Med. 2013; 79: 952-8.
+ Corresponding author: cvnakamura@uem.br 
https://orcid.org/https://orcid.org/0000-0002-9911-7369
Received 17 December 2021
Accepted 31 January 2022
