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

Perspectives for a new drug candidate for Chagas disease therapy

Maria de Nazaré Correia Soeiro+

Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Biologia Celular, Rio de Janeiro, RJ, Brasil

DOI: 10.1590/0074-02760220004
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ABSTRACT

Chagas disease (CD), a neglected tropical illness caused by the protozoan Trypanosoma cruzi, affects more than 6 million people mostly in poor areas of Latin America. CD has two phases: an acute, short phase mainly oligosymptomatic followed to the chronic phase, a long-lasting stage that may trigger cardiac and/or digestive disorders and death. Only two old drugs are available and both present low efficacy in the chronic stage, display side effects and are inactive against parasite strains naturally resistant to these nitroderivatives. These shortcomings justify the search for novel therapeutic options considering the target product profile for CD that will be presently reviewed besides briefly revisiting the data on phosphodiesterase inhibitors upon T. cruzi.

REFERENCES
01. WHO - World Health Organization [homepage on the Internet] [updated 2022, January 5]. Available from: https://www.who.int/ health-topics/chagas-disease#tab=tab_1.
02. DNDi.org [homepage on the Internet] [updated 2022, January 5]. Available from: https://dndi.org/diseases/chagas/.
03. Saraiva RM, Mediano MFF, Mendes FS, da Silva GMS, Veloso HH, Sangenis LHC, et al. Chagas heart disease: an overview of diagnosis, manifestations, treatment, and care. World J Cardiol. 2021; 13(12): 654-75.
04. Barrias E, Reignault LC, De Souza W. How does the main infective stage of T. cruzi enter and avoid degradation in host cells? A description of the pathways and organelles involved on these processes. IntechOpen. 2019; doi: http://dx.doi.org/10.5772/intechopen. 86046.
05. Nielebock MAP, Miranda LFC, Americano do Brasil PEA, Pereira TOJS, da Silva AF, Hasslocher-Moreno AM, et al. Blood culture positivity rate for Trypanosoma cruzi in patients with chronic Chagas disease differs among different clinical forms. Trans R Soc Trop Med Hyg. 2021; 115(6): 720-5.
06. Tarleton RL. Parasite persistence in the aetiology of Chagas disease. Int J Parasitol. 2001; 31(5-6): 550-4.
07. Pino-Marín A, Medina-Rincón GJ, Gallo-Bernal S, Duran-Crane A, Duque AIA, Rodríguez MJ, et al. Chagas cardiomyopathy: from Romaña sign to heart failure and sudden cardiac death. Pathogens. 2021; 10(5): 505.
08. Francisco AF, Jayawardhana S, Olmo F, Lewis MD, Wilkinson SR, Taylor CM, et al. Challenges in Chagas disease drug development. Molecules. 2020; 25: 2799.
09. Vannier-Santos MA, Brunoro GV, Soeiro MNC, DeCastro SL, Menna-Barreto R. Parasite, compartments, and molecules: trick versus treatment on Chagas disease. IntechOpen. 2019; DOI: http://dx.doi.org/10.5772/intechopen.84472.
10. Filardi LS, Brener Z. Susceptibility and natural resistance of Trypanosoma cruzi strains to drugs used clinically in Chagas disease. Trans R Soc Trop Med Hyg. 1987; 81(5): 755-9.
11. Zingales B, Andrade SG, Briones MRS, Campbell DA, Chiari E, Fernandes O, et al. A new consensus for Trypanosoma cruzi intraspecific nomenclature: second revision meeting recommends TcI to TcVI. Mem Inst Oswaldo Cruz. 2009; 104(7): 1051-4.
12. Zaidel EJ, Forsyth CJ, Novick G, Marcus R, Ribeiro ALP, Pinazo MJ, et al. COVID-19: implications for people with Chagas disease. Glob Heart. 2020; 15(1): 69.
13. Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi A, Rosas F, et al. Randomized trial of Benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med. 2015; 373: 1295-306.
14. Torrico F, Gascón J, Barreira F, Blum B, Almeida I, Alonso-Vega C, et al. New regimens of benznidazole monotherapy and in combination with fosravuconazole for treatment of Chagas disease (BENDITA): a phase 2, double-blind, randomised trial. Lancet Infect Dis. 2021; 21(8): 1129-40.
15. Molina-Morant D, Fernández ML, Bosch-Nicolau P, Sulleiro E, Bangher M, Salvador F, et al. Efficacy and safety assessment of different dosage of benznidazol for the treatment of Chagas disease in chronic phase in adults (MULTIBENZ study): study protocol for a multicenter randomized Phase II noninferiority clinical trial. Trials. 2020; 21: 328.
16. Cafferata M, Toscani MA, Althabe F, Belizán JM, Bergel E, Berrueta M, et al. Short-course Benznidazole treatment to reduce Trypanosoma cruzi parasitic load in women of reproductive age (BETTY): a noninferiority randomized controlled trial study protocol. Reprod Health. 2020; 17(1): 128.
17. Chatelain E, Scandale I. Animal models of Chagas disease and their translational value to drug development. Expert Opin Drug Discov. 2020; 15(12): 1381-402.
18. Kratz JM, Gonçalves KR, Romera LMD, Moraes CB, Bittencourt- Cunha P, Schenkman S, et al. The translational challenge in Chagas disease drug development. Mem Inst Oswaldo Cruz. 2021; 116: e200501.
19. Romanha AJ, DE Castro SL, Soeiro MNC, Lannes-Vieira J, Ribeiro I, Talvani A, et al. In vitro and in vivo experimental models for drug screening and development for Chagas disease. Mem Inst Oswaldo Cruz. 2010; 105(2): 233-8.
20. Lepesheva GI. Design or screening of drugs for the treatment of Chagas disease: what shows the most promise? Expert Opin Drug Discov. 2013; 8: 1479-89.
21. Molina I, Gómez i Prat J, Salvador F, Treviño B, Sulleiro E, Serre N, et al. Randomized trial of posaconazole and benznidazole for chronic Chagas’ disease. N Engl J Med. 2014; 370: 1899-908.
22. Lepesheva GI, Friggeri L, Waterman MR. CYP51 as drug targets for fungi and protozoan parasites: past, present and future. Parasitology. 2018; 145: 1820-36.
23. Soeiro MNC, de Souza EM, da Silva CF, Batista DG, Batista MM, Pavão BP, et al. In vitro and in vivo studies of the antiparasitic activity of sterol 14alpha-demethylase (CYP51) inhibitor VNI against drug-resistant strains of Trypanosoma cruzi. Antimicrob Agents Chemother. 2013; 57(9): 4151-63.
24. Guedes-da-Silva FH, Batista DG, Da Silva CF, De Araújo JS, Pavão BP, Simões-Silva MR, et al. Antitrypanosomal activity of sterol 14α-Demethylase (CYP51) inhibitors VNI and VFV in the Swiss mouse models of Chagas disease induced by the Trypanosoma cruzi y strain. Antimicrob Agents Chemother. 2017; 61(4): e02098-16.
25. Guedes-da-Silva FH, Batista DDGJ, Da Silva CF, Pavão BP, Batista MM, Moreira OC, et al. Successful aspects of the coadministration of sterol 14α-Demethylase inhibitor VFV and Benznidazole in experimental mouse models of Chagas disease caused by the drug-resistant strain of Trypanosoma cruzi. ACS Infect Dis. 2019; 5(3): 365-71.
26. Cal M, Ioset JR, Fügi MA, Mäser P, Kaiser M. Assessing anti-T. cruzi candidates in vitro for sterile cidality. Int J Parasitol Drugs Drug Resist. 2016; 6(3): 165-70.
27. Francisco AF, Lewis MD, Jayawardhana S, Taylor MC, Chatelain E, Kelly JM. Limited ability of posaconazole to cure both acute and chronic Trypanosoma cruzi infections revealed by highly sensitive in vivo imaging. Antimicrob Agents Chemother. 2015; 59(8): 4653-61.
28. MacLean LM, Thomas J, Lewis MD, Cotillo I, Gray DW, De Rycker M. Development of Trypanosoma cruzi in vitro assays to identify compounds suitable for progression in Chagas’ disease drug discovery. PLoS Negl Trop Dis. 2018; 12: e0006612.
29. Bouton J, Fiuza LFA, Cardoso-Santos C, Mazzarella MA, Soeiro MNC, Maes L, et al. Revisiting Pyrazolo[3,4- d]pyrimidine nucleosides as snti- Trypanosoma cruzi and antileishmanial agents. J Med Chem. 2021; 64(7): 4206-38.
30. Cardoso-Santos C, Fiuza LFA, da Silva CF, Mazzeti AL, Girão RD, de Oliveira GM, et al. 7-Aryl-7-deazapurine 3’-deoxyribonucleoside derivative as a novel lead for Chagas’ disease therapy: in vitro and in vivo pharmacology. JAC Antimicrob Resist. 2021; 3(4): dlab168.
31. Barrett MP, Kyle DE, Sibley LD, Radke JB, Tarleton RL. Protozoan persister-like cells and drug treatment failure. Nat Rev Microbiol. 2019; 17(10): 607-20.
32. Sánchez-Valdéz FJ, Padilla A, Wang W, Orr D, Tarleton RL. Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure. Elife. 2018; 7: e34039.
33. Bustamante JM, Sanchez-Valdez F, Padilla AM, White B, Wang W, Tarleton RL. A modified drug regimen clears active and dormant trypanosomes in mouse models of Chagas disease. Sci Transl Med. 2020; 12(567): eabb7656.
34. Franco CH, Alcântara LM, Chatelain E, Freitas-Junior L, Moraes CB. Drug discovery for Chagas disease: impact of different host cell lines on assay performance and hit dompound selection. Trop Med Infect Dis. 2019; 4(2): 82.
35. Souza EM, Lansiaux A, Bailly C, Wilson WD, Huc Q, Boykin D, et al. Phenyl substitution of furamidine markedly potentiates its anti-parasitic activity against Trypanosoma cruzi and Leishmania amazonensis. Biochem Pharmacol. 2004; 68: 593-600.
36. Fiuza LA, Batista DGJ, Nunes DF, Moreira OC, Cascabulho C, Soeiro MNC. Benznidazole modulates release of inflammatory mediators by cardiac spheroids infected with Trypanosoma cruzi. Exp Parasitol. 2021; 221: 108061.
37. Fertig BA, Baillie GS. PDE4-mediated cAMP signalling. J Cardiovasc Dev Dis. 2018; 5: 8.
38. Johnstone TB, Agarwal SR, Harvey RD, Ostrom RS. cAMP signaling compartmentation: adenylyl cyclases as anchors of dynamic signaling complexes. Mol Pharmacol. 2018; 93: 270-6.
39. Gould MK, de Koning HP. Cyclic-nucleotide signalling in protozoa. FEMS Microbiol Rev. 2011; 35: 515-41.
40. Tagoe DN, Kalejaiye TD, de Koning HP. The ever unfolding story of cAMP signaling in trypanosomatids: vive la difference! Front Pharmacol. 2015; 6: 185.
41. de Koning HP, Gould MK, Sterk GJ, Tenor H, Kunz S, Luginbuehl E, et al. Pharmacological validation of Trypanosoma brucei phosphodiesterases as novel drug targets. J Infect Dis. 2012; 206(2): 229-37.
42. De Araujo JS, da Silva PB, Batista MM, Peres RB, Cardoso-Santos C, Kalejaiye TD, et al. Evaluation of phthalazinone phosphodiesterase inhibitors with improved activity and selectivity against Trypanosoma cruzi. J Antimicrob Chemother. 2020; 75: 958-67.
43. de Araújo JS, Peres RB, da Silva PB, Batista MM, Sterk GJ, Maes L, et al. Tetrahydrophthalazinone inhibitor of phosphodiesterase with in vitro activity against intracellular trypanosomatids. Antimicrob Agents Chemother. 2021; 65: e00960-20.
44. de Araújo JS, da Silva CF, Batista DGJ, Nefertiti A, Fiuza LFA, Fonseca-Berzal CR, et al. Efficacy of novel pyrazolone phosphodiesterase inhibitors in experimental mouse models of Trypanosoma cruzi. Antimicrob Agents Chemother. 2020; 64(9): e00414-20.
45. Schoijet AC, Miranda K, Medeiros LC, de Souza W, Flawia MM, Torres HN, et al. Defining the role of a FYVE domain in the localization and activity of a cAMP phosphodiesterase implicated in osmoregulation in Trypanosoma cruzi. Mol Microbiol. 2011; 79: 50-62.
46. de Araújo JS, García-Rubia A, Sebastián-Pérez V, Kalejaiye TD, da Silva PB, Fonseca-Berzal CR, et al. Imidazole derivatives as promising agents for the treatment of Chagas disease. Antimicrob Agents Chemother. 2019; 63(4): e02156-18.
47. Blokland A, Heckman P, Vanmierlo T, Schreiber R, Paes D, Prickaerts J. Phosphodiesterase type 4 inhibition in CNS diseases. Trends Pharmacol Sci. 2019; 40(12): 971-85.

Financial support: Grants from FAPERJ, CNPq, PAEF, FIOCRUZ.
MNCS is research fellow of the CNPq and Cientista do Nosso Estado da FAPERJ.
+ Corresponding author: soeiro@ioc.fiocruz.br
ORCID https://orcid.org/0000-0003-0078-6106
Received 06 January 2022
Accepted 17 January 2022

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