Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 117 | 2022

Antileishmanial metallodrugs and the elucidation of new drug targets linked to post-translational modifications machinery: pitfalls and progress

Rubens Lima do Monte Neto1,+, Paulo Otávio Lourenço Moreira1, Alessandra Mara de Sousa1, Miguel Antonio do Nascimento Garcia2, Suellen Rodrigues Maran2, Nilmar Silvio Moretti2,+

1Fundação Oswaldo Cruz-Fiocruz, Instituto René Rachou, Grupo de Pesquisas em Biotecnologia Aplicada ao Estudo de Patógenos, Belo Horizonte, MG, Brasil
2Universidade Federal de São Paulo, Departamento de Microbiologia, Imunologia e Parasitologia, Laboratório de Biologia Molecular de Patógenos, São Paulo, SP, Brasil

DOI: 10.1590/0074-02760220403
3584 views 235 downloads

Despite the increasing number of manuscripts describing potential alternative antileishmanial compounds, little is advancing on translating these knowledges to new products to treat leishmaniasis. This is in part due to the lack of standardisations during pre-clinical drug discovery stage and also depends on the alignment of goals among universities/research centers, government and pharmaceutical industry. Inspired or not by drug repurposing, metal-based antileishmanial drugs represent a class that deserves more attention on its use for leishmaniasis chemotherapy. Together with new chemical entities, progresses have been made on the knowledge of parasite-specific drug targets specially after using CRISPR/Cas system for functional studies. In this regard, Leishmania parasites undergoe post-translational modification as key regulators in several cellular processes, which represents an entire new field for drug target elucidation, once this is poorly explored. This perspective review describes the advances on antileishmanial metallodrugs and the elucidation of drug targets based on post-translational modifications, highlighting the limitations on the drug discovery/development process and suggesting standardisations focused on products addressed to who need it most.

01. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007; 7(8): 573-84.

02. Wheate NJ, Walker S, Craig GE, Oun R. The status of platinum anticancer drugs in the clinic and in clinical trials. Dalton Trans. 2010; 39(35): 8113-27.

03. Haldar AK, Sen P, Roy S. Use of antimony in the treatment of leishmaniasis: current status and future directions. Mol Biol Int. 2011; 2011: e571242.

04. Bhargava P, Singh R. Developments in diagnosis and antileishmanial drugs. Interdiscip Perspect Infect Dis. 2012; 2012: 626838.

05. Haas KL, Franz KJ. Application of metal coordination chemistry to explore and manipulate cell biology. Chem Rev. 2009; 109(10): 4921-60.

06. Wang X, Wang X, Jin S, Muhammad N, Guo Z. Stimuli-responsive therapeutic metallodrugs. Chem Rev. 2019; 119(2): 1138-92.

07. Frezza M, Hindo S, Chen D, Davenport A, Schmitt S, Tomco D, et al. Novel metals and metal complexes as platforms for cancer therapy. Curr Pharm Des. 2010; 16(16): 1813-25.

08. Nriagu JO, Skaar EP, editors. Trace metals and infectious diseases [Internet]. Cambridge (MA): MIT Press; 2015 [cited 2021]. Available from:

09. Boros E, Dyson PJ, Gasser G. Classification of metal-based drugs according to their mechanisms of action. Chem. 2020; 6(1): 41-60.

10. Ong YC, Kedzierski L, Andrews PC. Do bismuth complexes hold promise as antileishmanial drugs? Future Med Chem. 2018; 10(14): 1721-33.

11. Costa MS, Gonçalves YG, Teixeira SC, Nunes DCO, Lopes DS, da Silva CV, et al. Increased ROS generation causes apoptosis-like death: mechanistic insights into the anti-Leishmania activity of a potent ruthenium(II) complex. J Inorg Biochem. 2019; 195: 1-12.

12. Iniguez E, Varela-Ramirez A, Martínez A, Torres CL, Sánchez- -Delgado RA, Maldonado RA. Ruthenium-clotrimazole complex has significant efficacy in the murine model of cutaneous leishmaniasis. Acta Trop. 2016; 164: 402-10.

13. Caballero AB, Salas JM, Sánchez-Moreno M. Metal-based therapeutics for leishmaniasis [Internet]. Leishmaniasis - Trends in epidemiology, diagnosis and treatment. IntechOpen. 2014 [cited 2021]. Available from:
14. Ilari A, Baiocco P, Messori L, Fiorillo A, Boffi A, Gramiccia M, et al. A gold-containing drug against parasitic polyamine metabolism: the X-ray structure of trypanothione reductase from Leishmania infantum in complex with auranofin reveals a dual mechanism of enzyme inhibition. Amino Acids. 2012; 42(2-3): 803-11.

15. Sharlow ER, Leimgruber S, Murray S, Lira A, Sciotti RJ, Hickman M, et al. Auranofin is an apoptosis-simulating agent with in vitro and in vivo anti-leishmanial activity. ACS Chem Biol. 2014; 9(3): 663-72.

16. Chaves JDS, Tunes LG, Franco CHJ, Francisco TM, Corrêa CC, Murta SMF, et al. Novel gold(I) complexes with 5-phenyl-1,3,4- oxadiazole-2-thione and phosphine as potential anticancer and antileishmanial agents. Eur J Med Chem. 2017; 127: 727-39.

17. Tunes LG, Morato RE, Garcia A, Schmitz V, Steindel M, Corrêa- Junior JD, et al. Preclinical gold complexes as oral drug candidates to treat leishmaniasis are potent trypanothione reductase inhibitors. ACS Infect Dis. 2020; 6(5): 1121-39.

18. Rosa LB, Aires RL, Oliveira LS, Fontes JV, Miguel DC, Abbehausen C. A “Golden Age” for the discovery of new antileishmanial agents: current status of leishmanicidal gold complexes and prospective targets beyond the trypanothione system. ChemMed- Chem. 2021; 16(11): 1682-96.

19. Alcolea V, Moreno E, Etxebeste-Mitxeltorena M, Navarro-Blasco I, González-Peñas E, Jiménez-Ruiz A, et al. 3,5-Dimethyl-4-isoxazoyl selenocyanate as promising agent for the treatment of Leishmania infantum-infected mice. Acta Trop. 2021; 215: 105801.

20. do Nascimento NRF, de Aguiar FLN, Santos CF, Costa AML, Hardoim DJ, Calabrese KS, et al. In vitro and in vivo leishmanicidal activity of a ruthenium nitrosyl complex against Leishmania (Viannia) braziliensis. Acta Trop. 2019; 192: 61-5.

21. Segura DF, Netto AVG, Frem RCG, Mauro AE, da Silva PB, Fernandes JA, et al. Synthesis and biological evaluation of ternary silver compounds bearing N,N-chelating ligands and thiourea: Xray structure of [{Ag(bpy)(μ-tu)}2](NO3)2 (bpy=2,2′-bipyridine; tu=thiourea). Polyhedron. 2014; 79: 197-206.
22. Navarro M, Cisneros-Fajardo EJ, Marchan E. New silver polypyridyl complexes: synthesis, characterization and biological activity on Leishmania mexicana. Arzneimittelforschung. 2006; 56(8): 600-4.

23. Mukhopadhyay R, Madhubala R. Effect of antioxidants on the growth and polyamine levels of Leishmania donovani. Biochem Pharmacol. 1994; 47(4): 611-5.

24. Beheshti N, Soflaei S, Shakibaie M, Yazdi MH, Ghaffarifar F, Dalimi A, et al. Efficacy of biogenic selenium nanoparticles against Leishmania major: in vitro and in vivo studies. J Trace Elem Med Biol. 2013; 27(3): 203-7.

25. Das S, Roy P, Mondal S, Bera T, Mukherjee A. One pot synthesis of gold nanoparticles and application in chemotherapy of wild and resistant type visceral leishmaniasis. Colloids Surf B Biointerfaces. 2013; 107: 27-34.

26. Baiocco P, Ilari A, Ceci P, Orsini S, Gramiccia M, Di Muccio T, et al. Inhibitory effect of silver nanoparticles on trypanothione reductase activity and Leishmania infantum proliferation. ACS Med Chem Lett. 2010; 2(3): 230-3.

27. Allahverdiyev AM, Abamor ES, Bagirova M, Baydar SY, Ates SC, Kaya F, et al. Investigation of antileishmanial activities of Tio2@Ag nanoparticles on biological properties of L. tropica and L. infantum parasites, in vitro. Exp Parasitol. 2013; 135(1): 55-63.

28. Bafghi AF, Daghighi M, Daliri K, Jebali A. Magnesium oxide nanoparticles coated with glucose can silence important genes of Leishmania major at sub-toxic concentrations. Colloids Surf B Biointerfaces. 2015; 136: 300-4.

29. Rauf MK, Yaseen S, Badshah A, Zaib S, Arshad R, Imtiaz-Ud- Din null, et al. Synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of Ni(II) complexes with N,N,N’-trisubstituted thioureas. J Biol Inorg Chem. 2015; 20(3): 541-54.

30. Yaseen S, Rauf MK, Zaib S, Badshah A, Tahir MN, Ali MI, et al. Synthesis, characterization and urease inhibition, in vitro anticancer and antileishmanial studies of Co(III) complexes with N,N,N′-trisubstituted acylthioureas. Inorganica Chim Acta. 2016; 443: 69-77.

31. Machado PA, Morais JOF, Carvalho GSG, Lima WP, Macedo GC, Britta EA, et al. VOSalophen: a vanadium complex with a stilbene derivative — induction of apoptosis, autophagy, and efficiency in experimental cutaneous leishmaniasis. J Biol Inorg Chem. 2017; 22(6): 929-39.

32. Levina A, Crans DC, Lay PA. Speciation of metal drugs, supplements and toxins in media and bodily fluids controls in vitro activities. Coord Chem Rev. 2017; 352: 473-98.
33. Rosa-Teijeiro C, Wagner V, Corbeil A, d’Annessa I, Leprohon P, do Monte-Neto RL, et al. Three different mutations in the DNA topoisomerase 1B in Leishmania infantum contribute to resistance to antitumor drug topotecan. Parasit Vectors. 2021; 14(1): 438.

34. Pires DEV, Blundell TL, Ascher DB. pkCSM: predicting smallmolecule pharmacokinetic and toxicity properties using graphbased signatures. J Med Chem. 2015; 58(9): 4066-72.

35. Wagner V, Douanne N, Fernandez-Prada C. Leishmania infantum infection in a dog imported from Morocco. Can Vet J. 2020; 61(9): 963-5.

36. Beneke T, Madden R, Makin L, Valli J, Sunter J, Gluenz E. A CRISPR Cas9 high-throughput genome editing toolkit for kinetoplastids. R Soc Open Sci. 2017; 4(5): 170095.

37. Yagoubat A, Crobu L, Berry L, Kuk N, Lefebvre M, Sarrazin A, et al. Universal highly efficient conditional knockout system in Leishmania, with a focus on untranscribed region preservation. Cell Microbiol. 2020; 22(5): e13159.

38. Baker N, Catta-Preta CMC, Neish R, Sadlova J, Powell B, Alves- Ferreira EVC, et al. Systematic functional analysis of Leishmania protein kinases identifies regulators of differentiation or survival. Nat Commun. 2021; 12(1): 1244.

39. Jones CD, Andrews DM, Barker AJ, Blades K, Byth KF, Finlay MRV, et al. Imidazole pyrimidine amides as potent, orally bioavailable cyclin-dependent kinase inhibitors. Bioorganic Med Chem Lett. 2008; 18(24): 6486-9.

40. Thornton JM, Laskowski RA, Borkakoti N. AlphaFold heralds a data-driven revolution in biology and medicine. Nat Med. 2021; 27(10): 1666-9.

41. Humphrey SJ, James DE, Mann M. Protein phosphorylation: a major switch mechanism for metabolic regulation. Trends Endocrinol Metab. 2015; 26(12): 676-87.

42. Wu Z, Connolly J, Biggar KK. Beyond histones - the expanding roles of protein lysine methylation. FEBS J. 2017; 284(17): 2732-44.

43. Mansour MA. Ubiquitination: friend and foe in cancer. Int J Biochem Cell Biol. 2018; 101: 80-93.

44. Narita T, Weinert BT, Choudhary C. Functions and mechanisms of non-histone protein acetylation. Nat Rev Mol Cell Biol. 2019; 20(3): 156-74.

45. Li K, Wang Z. Histone crotonylation-centric gene regulation. Epigenetics Chromatin. 2021; 14(1): 10.

46. Hem S, Gherardini PF, Osorio y Fortéa J, Hourdel V, Morales MA, Watanabe R, et al. Identification of Leishmania-specific protein phosphorylation sites by LC-ESI-MS/MS and comparative genomics analyses. Proteomics. 2010; 10(21): 3868-83.

47. Tsigankov P, Gherardini PF, Helmer-Citterich M, Späth GF, Myler PJ, Zilberstein D. Regulation dynamics of Leishmania differentiation: deconvoluting signals and identifying phosphorylation trends. Mol Cell Proteomics. 2014; 13(7): 1787-99.

48. Moretti NS, Cestari I, Anupama A, Stuart K, Schenkman S. Comparative proteomic analysis of lysine acetylation in trypanosomes. J Proteome Res. 2018; 17(1): 374-85.

49. Zhang N, Jiang N, Zhang K, Zheng L, Zhang D, Sang X, et al. Landscapes of protein posttranslational modifications of African Trypanosoma parasites. iScience. 2020; 23(5): 101074.

50. Bonne Køhler J, Jers C, Senissar M, Shi L, Derouiche A, Mijakovic I. Importance of protein Ser/Thr/Tyr phosphorylation for bacterial pathogenesis. FEBS Lett. 2020; 594(15): 2339-69.

51. Huang B, Zhao Z, Zhao Y, Huang S. Protein arginine phosphorylation in organisms. Int J Biol Macromol. 2021; 171: 414-22.

52. Morales MA, Watanabe R, Dacher M, Chafey P, Osorio y Fortéa J, Scott DA, et al. Phosphoproteome dynamics reveal heat-shock protein complexes specific to the Leishmania donovani infectious stage. Proc Natl Acad Sci USA. 2010; 107(18): 8381-6.

53. Wu P, Nielsen TE, Clausen MH. FDA-approved small-molecule kinase inhibitors. Trends Pharmacol Sci. 2015; 36(7): 422-39.

54. Parsons M, Worthey EA, Ward PN, Mottram JC. Comparative analysis of the kinomes of three pathogenic trypanosomatids: Leishmania major, Trypanosoma brucei and Trypanosoma cruzi. BMC Genomics. 2005; 6: 127.

55. Borba JVB, Silva AC, Ramos PIP, Grazzia N, Miguel DC, Muratov EN, et al. Unveiling the kinomes of Leishmania infantum and L. braziliensis empowers the discovery of new kinase targets and antileishmanial compounds. Comput Struct Biotechnol J. 2019; 17: 352-61.

56. Naula C, Parsons M, Mottram JC. Protein kinases as drug targets in trypanosomes and Leishmania. Biochim Biophys Acta. 2005; 1754(1-2): 151-9.

57. Efstathiou A, Smirlis D. Leishmania protein kinases: important regulators of the parasite life cycle and molecular targets for treating leishmaniasis. Microorganisms. 2021; 9(4): 691.

58. Wyllie S, Thomas M, Patterson S, Crouch S, De Rycker M, Lowe R, et al. Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature. 2018; 560(7717): 192-7.

59. Ree R, Varland S, Arnesen T. Spotlight on protein N-terminal acetylation. Exp Mol Med. 2018; 50(7): 1-13.

60. Leite AB, Gomes AAS, Sousa ACCN, Fontes MRM, Schenkman S, Moretti NS. Effect of lysine acetylation on the regulation of Trypanosoma brucei glycosomal aldolase activity. Biochem J. 2020; 477(9): 1733-44.

61. Moura LS, Nunes VS, Gomes AAS, Sousa ACCN, Fontes MRM, Schenkman S, et al. Mitochondrial sirtuin TcSir2rp3 affects Tc- SODA activity and oxidative stress response in Trypanosoma cruzi. Front Cell Infect Microbiol. 2021; 11: 773410.
62. Maran SR, Fleck K, Monteiro-Teles NM, Isebe T, Walrad P, Jeffers V, et al. Protein acetylation in the critical biological processes in protozoan parasites. Trends Parasitol. 2021; 37(9): 815-30.
63. Seto E, Yoshida M. Erasers of histone acetylation: the histone deacetylase enzymes. Cold Spring Harb Perspect Biol. 2014; 6(4): a018713.
64. Marmorstein R, Zhou M-M. Writers and readers of histone acetylation: structure, mechanism, and inhibition. Cold Spring Harb Perspect Biol. 2014; 6(7): a018762.
65. Fujisawa T, Filippakopoulos P. Functions of bromodomain-containing proteins and their roles in homeostasis and cancer. Nat Rev Mol Cell Biol. 2017; 18(4): 246-62.
66. Peralta GM, Serra E, Alonso VL. Update on the biological relevance of lysine acetylation as a novel drug target in trypanosomatids. Curr Med Chem. 2021; doi: 10.2174/0929867328666211126145721.
67. Tallant C, Bamborough P, Chung C-W, Gamo FJ, Kirkpatrick R, Larminie C, et al. Expanding bromodomain targeting into neglected parasitic diseases. ACS Infect Dis. 2021; 7(11): 2953-8.
68. Vergnes B, Sereno D, Tavares J, Cordeiro-da-Silva A, Vanhille L, Madjidian-Sereno N, et al. Targeted disruption of cytosolic SIR2 deacetylase discloses its essential role in Leishmania survival and proliferation. Gene. 2005; 363: 85-96.
69. Vergnes B, Gazanion E, Grentzinger T. Functional divergence of SIR2 orthologs between trypanosomatid parasites. Mol Biochem Parasitol. 2016; 207(2): 96-101.
70. Tavares J, Ouaissi A, Santarém N, Sereno D, Vergnes B, Sampaio P, et al. The Leishmania infantum cytosolic SIR2-related protein 1 (LiSIR2RP1) is an NAD+ -dependent deacetylase and ADPribosyltransferase. Biochem J. 2008; 415(3): 377-86.
71. Kadam RU, Tavares J, Kiran VM, Cordeiro A, Ouaissi A, Roy N. Structure function analysis of Leishmania sirtuin: an ensemble of in silico and biochemical studies. Chem Biol Drug Des. 2008; 71(5): 501-6.
72. Sodji Q, Patil V, Jain S, Kornacki JR, Mrksich M, Tekwani BL, et al. The antileishmanial activity of isoforms 6- and 8-selective histone deacetylase inhibitors. Bioorg Med Chem Lett. 2014; 24(20): 4826-30.
73. Jones NG, Geoghegan V, Moore G, Carnielli JBT, Newling K, Calderón F, et al. Bromodomain factor 5 is an essential transcriptional regulator of the Leishmania genome [Internet]. 2021 Sep [cited 2021] p. 2021.09.29.462384. Available from: https://www.
74. Stathis A, Bertoni F. BET proteins as targets for anticancer treatment. Cancer Discov. 2018; 8(1): 24-36.
75. Azevedo C, Saiardi A. Why always lysine? The ongoing tale of one of the most modified amino acids. Adv Biol Regul. 2016; 60: 144-50.
76. Sabari BR, Zhang D, Allis CD, Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat Rev Mol Cell Biol. 2017; 18(2): 90-101.
77. Bao X, Wang Y, Li X, Li X-M, Liu Z, Yang T, et al. Identification of “erasers” for lysine crotonylated histone marks using a chemical proteomics approach. Elife. 2014; 3.
78. Huang H, Wang D-L, Zhao Y. Quantitative crotonylome analysis expands the toles of p300 in the regulation of lysine crotonylation pathway. Proteomics. 2018; 18(15): e1700230.
79. Kollenstart L, de Groot AJL, Janssen GMC, Cheng X, Vreeken K, Martino F, et al. Gcn5 and Esa1 function as histone crotonyltransferases to regulate crotonylation-dependent transcription. J Biol Chem. 2019; 294(52): 20122-34.
80. Abu-Zhayia ER, Machour FE, Ayoub N. HDAC-dependent decrease in histone crotonylation during DNA damage. J Mol Cell Biol. 2019; 11(9): 804-6.
81. Andrews FH, Shinsky SA, Shanle EK, Bridgers JB, Gest A, Tsun IK, et al. The Taf14 YEATS domain is a reader of histone crotonylation. Nat Chem Biol. 2016; 12(6): 396-8.
82. Li Y, Wen H, Xi Y, Tanaka K, Wang H, Peng D, et al. AF9 YEATS domain links histone acetylation to DOT1L-mediated H3K79 methylation. Cell. 2014; 159(3): 558-71.
83. Shanle EK, Andrews FH, Meriesh H, McDaniel SL, Dronamraju R, DiFiore JV, et al. Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response. Genes Dev. 2015; 29(17): 1795-800.
84. Fleck K, Nitz M, Jeffers V. “Reading” a new chapter in protozoan parasite transcriptional regulation. PLoS Pathog. 2021; 17(12): e1010056.
85. Schulze JM, Wang AY, Kobor MS. YEATS domain proteins: a diverse family with many links to chromatin modification and transcription. Biochem Cell Biol. 2009; 87(1): 65-75.
86. Wang Q, Verma J, Vidan N, Wang Y, Tucey TM, Lo TL, et al. The YEATS domain histone crotonylation readers control virulence- related biology of a major human pathogen. Cell Rep. 2020; 31(3): 107528.
87. Moustakim M, Christott T, Monteiro OP, Bennett J, Giroud C, Ward J, et al. Discovery of an MLLT1/3 YEATS domain chemical probe. Angew Chem Int Ed Engl. 2018; 57(50): 16302-7.
88. Garnar-Wortzel L, Bishop TR, Kitamura S, Milosevich N, Asiaban JN, Zhang X, et al. Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia. ACS Cent Sci. 2021; 7(5): 815-30.
89. Ma XR, Xu L, Xu S, Klein BJ, Wang H, Das S, et al. Discovery of selective small-molecule inhibitors for the ENL YEATS domain. J Med Chem. 2021; 64(15): 10997-1013.
90. Pahlich S, Zakaryan RP, Gehring H. Protein arginine methylation: cellular functions and methods of analysis. Biochim Biophys Acta. 2006; 1764(12): 1890-903.
91. Ferreira TR, Alves-Ferreira EVC, Defina TPA, Walrad P, Papadopoulou B, Cruz AK. Altered expression of an RBP-associated arginine methyltransferase 7 in Leishmania major affects parasite infection. Mol Microbiol. 2014; doi: 10.1111/mmi.12819.
92. Ferreira TR, Dowle AA, Parry E, Alves-Ferreira EVC, Hogg K, Kolokousi F, et al. PRMT7 regulates RNA-binding capacity and protein stability in Leishmania parasites. Nucleic Acids Res. 2020; 48(10): 5511-26.
93. Bijlmakers M-J. Ubiquitination and the proteasome as drug targets in trypanosomatid diseases. Front Chem. 2020; 8: 630888.
94. Damianou A, Burge RJ, Catta-Preta CMC, Geoghegan V, Nievas YR, Newling K, et al. Essential roles for deubiquitination in Leishmania life cycle progression. PLoS Pathog. 2020; 16(6): e1008455.
95. Burge RJ, Damianou A, Wilkinson AJ, Rodenko B, Mottram JC. Leishmania differentiation requires ubiquitin conjugation mediated by a UBC2-UEV1 E2 complex. PLoS Pathog. 2020; 16(10): e1008784.
96. Wani R, Nagata A, Murray BW. Protein redox chemistry: posttranslational cysteine modifications that regulate signal transduction and drug pharmacology. Front Pharmacol. 2014; 5: 224.
97. Lyu W, Arnesano F, Carloni P, Natile G, Rossetti G. Effect of in vivo post-translational modifications of the HMGB1 protein upon binding to platinated DNA: a molecular simulation study. Nucleic Acids Res. 2018; 46(22): 11687-97.

Financial support: FAPESP (grant 2018/09948-0 and 2020/07870-4 to NSM and 2019/13765-1 to SRM and 2020/04748-6 to MANG), CNPq (grant 424729/2018-0 to NM).
POLM and AMS hold PhD fellowships from CAPES/Proex (process numbers 88887.473451/2020-00; 88887.604141/2021-00). This study was financed in part by the CAPES, Fapemig (grant PPM-00699-18 to RMN). NSM and RMN are CNPq research fellow (CNPq: 314103/2021-0 and 312965/2020-6).
+ Corresponding authors: /
Received 21 December 2021
Accepted 17 January 2022

Our Location

Memórias do Instituto Oswaldo Cruz

Av. Brasil 4365, Castelo Mourisco 
sala 201, Manguinhos, 21040-900 
Rio de Janeiro, RJ, Brazil

Tel.: +55-21-2562-1222

This email address is being protected from spambots. You need JavaScript enabled to view it.

Support Program


faperj cnpq capes