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

Repositioning drug strategy against Trypanosoma cruzi: lessons learned from HIV aspartyl peptidase inhibitors

Leandro Stefano Sangenito1,+, Claudia Masini d’Avila-Levy2, Marta Helena Branquinha1, André Luis Souza dos Santos1,3

1Universidade Federal do Rio de Janeiro, Instituto de Microbiologia Paulo de Góes, Departamento de Microbiologia Geral, Laboratório de Estudos Avançados de Microrganismos Emergentes e Resistentes, Rio de Janeiro, RJ, Brasil
2Fundação Oswaldo Cruz-Fiocruz, Instituto Oswaldo Cruz, Laboratório de Estudos Integrados em Protozoologia, Rio de Janeiro, RJ, Brasil
3Universidade Federal do Rio de Janeiro, Instituto de Química, Programa de Pós-Graduação em Bioquímica, Rio de Janeiro, RJ, Brasil

DOI: 10.1590/0074-02760210386
712 views 199 downloads
ABSTRACT

Chagas disease (CD) is an old neglected problem that affects more than 6 million people through 21 endemic countries in Latin America. Despite being responsible for more than 12 thousand deaths per year, the disease disposes basically of two drugs for its treatment, the nitroimidazole benznidazole and the nitrofuran nifurtimox. However, these drugs have innumerous limitations that greatly reduce the chances of cure. In Brazil, for example, only benznidazole is available to treat CD patients. Therefore, some proof-of-concept phase II clinical trials focused on improving the current treatment with benznidazole, also comparing it with repositioned drugs or combining them. Indeed, repositioning already marketed drugs in view of combating neglected tropical diseases is a very interesting approach in the context of decreased time for approval, better treatment options and low cost for development and implementation. After the introduction of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) in the treatment of acquired immune deficiency syndrome (AIDS), the prevalence and incidence of parasitic, fungal and bacterial co-infections suffered a marked reduction, making these HIV-PIs attractive for drug repositioning. In this line, the present perspective presents the promising and beneficial data concerning the effects of HIV-PIs on the clinically relevant forms of Trypanosoma cruzi (i.e., trypomastigotes and amastigotes) and also highlights the ultrastructural and physiological targets for the HIV-PIs on this parasite. Therefore, we raise the possibility that HIV-PIs could be considered as alternative treatment options in the struggle against CD.

REFERENCES
01. WHO - World Health Organization. Chagas disease (American trypanosomiasis). 2021. Available from: https://www.who.int/ news-room/fact-sheets/detail/chagas-disease-(american-trypanosomiasis)
02. Lidani KCF, Andrade FA, Bavia L, Damasceno FS, Beltrame MH, Messias-Reason IJ, et al. Chagas disease: from discovery to a worldwide health problem. Front Public Health. 2019; 2: 166.
03. WHO - World Health Organization. Investing to overcome the global impact of neglected tropical diseases: third WHO report on neglected diseases. Library Cataloguing-in-Publication Data. 2015; 2: 75-81.
04. Pinheiro E, Brum-Soares L, Reis R, Cubides JC. Chagas disease: review of needs, neglect, and obstacles to treatment access in Latin America. Rev Soc Bras Med Trop. 2017; 50(3): 296-300.
05. DNDi - Drugs for Neglected Diseases initiative. Chagas disease. 2021. Available from: https://dndi.org/diseases/chagas/facts/.
06. Lee BY, Bacon KM, Bottazzi ME, Hotez PJ. Global economic burden of Chagas disease: a computational simulation model. Lancet Infect Dis. 2013; 13(4): 342-8.
07. Ferreira LG, de Oliveira MT, Andricopulo AD. Advances and progress in Chagas disease drug discovery. Curr Top Med Chem. 2016; 16(20): 2290-302.
08. Sangenito LS, Branquinha MH, Santos ALS. Funding for Chagas disease: a 10-year (2009-2018) survey. Trop Med Infect Dis. 2020; 5(2): 88.
09. Mendes FSNS, Perez-Molina JA, Angheben A, Meymandi SK, Sosa- Estani S, Molina I. Critical analysis of Chagas disease treatment in different countries. Mem Inst Oswaldo Cruz. 2021; 116: e210034.
10. Sangenito LS, Santos VS, d’Avila-Levy CM, Branquinha MH, Santos ALS, Oliveira SSC. Leishmaniasis and Chagas disease - neglected tropical diseases: treatment updates. Curr Top Med Chem. 2019; 19(3): 174-7.
11. Arrowsmith J, Harrison R. Drug repositioning: the business case and current strategies to repurpose shelved candidates and marketed drugs. John Wiley Sons, Inc.: 2012; 7-32.
12. Nosengo N. Can you teach old drugs new tricks? Nature. 2016; 534(7607): 314-6.
13. Sbaraglin ML, Vanrell MC, Bellera CL, Benaim G, Carrillo C, Talevi A, et al. Neglected tropical protozoan diseases: drug repositioning as a rational option. Curr Top Med Chem. 2016; 16(19): 2201-22.
14. Ferreira LG, Andricopulo AD. Drug repositioning approaches to parasitic diseases: a medicinal chemistry perspective. Drug Discov Today. 2016; 21(10): 1699-710.
15. Yella JK, Yaddanapudi S, Wang Y, Jegga AG. Changing trends in computational drug repositioning. Pharmaceuticals (Basel). 2018; 11: E57.
16. Zhan P, Pannecouque C, De Clercq E, Liu X. Anti-HIV drug discovery and development: current innovations and future trends. J Med Chem. 2016; 59(7): 2849-78.
17. Tsantrizos YS. Peptidomimetic therapeutic agents targeting the protease enzyme of the human immunodeficiency virus and hepatitis C virus. Chem Res. 2008; 41(10): 1252-63.
18. Ebrahim O, Mazanderani AH. Recent developments in HIV treatment and their dissemination in poor countries. Infect Dis Rep. 2013; 5: e2.
19. Mastrolorenzo A, Rusconi S, Scozzafava A, Barbaro G, Supuran CT. Inhibitors of HIV-1 protease: current state of the art 10 years after their introduction. From antiretroviral drugs to antifungal, antibacterial and antitumor agents based on aspartic protease inhibitors. Curr Med Chem. 2007; 14(26); 2734-48.
20. Alfonso Y, Monzote L. HIV protease inhibitors: effect on the opportunistic protozoan parasites. Open Med Chem J. 2011; 5: 40-50.
21. Santos ALS, d’Avila-Levy CM, Kneipp LF, Sodré CL, Sangenito LS, Branquinha MH. The widespread anti-protozoal action of HIV aspartic peptidase inhibitors: focus on Plasmodium spp., Leishmania spp. and Trypanosoma cruzi. Curr Top Med Chem. 2017; 17(11): 1303-17.
22. Pintado V, Martín-Rabadán P, Rivera ML, Moreno S, Bouza E. Visceral leishmaniasis in human immunodeficiency virus (HIV)- infected and non HIV infected patients. A comparative study. Medicine. 2001; 80(1): 54-73.
23. Corti M, Yampolsky C. Prolonged survival and immune reconstitution after chagasic meningoencephalitis in a patient with acquired immunodeficiency syndrome. Rev Soc Bras Med Trop. 2006; 39(1): 85-8.
24. Pérez-Molina JA. Management of Trypanosoma cruzi coinfection in HIV-positive individuals outside endemic areas. Curr Opin Infect Dis. 2014; 27(1): 9-15.
25. Sangenito LS, Menna-Barreto RF, d’Avila-Levy CM, Santos ALS, Branquinha MH. Decoding the anti-Trypanosoma cruzi action of HIV peptidase inhibitors using epimastigotes as a model. PLoS One. 2014: 9; e113957.
26. Sangenito LS, Gonçalves DS, Seabra SH, d’Avila-Levy CM, Santos ALS, Branquinha MH. HIV aspartic peptidase inhibitors are effective drugs against the trypomastigote form of the human pathogen Trypanosoma cruzi. Int J Antimicrob Agents. 2016; 48(4): 440-4.
27. El-Sayed NM, Myler PJ, Bartholomeu DC, Nilsson D, Aggarwal G, Tran AN, et al. The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas’ disease. Science. 2005; 309(5733): 409-15.
28. Pinho RT, Beltramini LM, Alves CR, Giovanni-De-Simone S. Trypanosoma cruzi: isolation and characterization of aspartyl proteases. Exp Parasitol. 2009; 122(2): 128-33.
29. Lechuga GC, Napoleão-Pêgo P, Bottino CCG, Pinho RT, Provance-Jr DW, De-Simone SG. Trypanosoma cruzi presenilinlike transmembrane aspartyl protease: characterization and cellular localization. Biomolecules. 2020; 10(11): 1564.
30. Castilho VVS, Gonçalves KCS, Rebello KM, Baptista LPR, Sangenito LS, Santos HLC, et al. Docking simulation between HIV peptidase inhibitors and Trypanosoma cruzi aspartyl peptidase. BMC Res Notes. 2018; 11(1): 825.
31. Piccinini M, Rinaudo MT, Anselmino A, Buccinnà B, Ramondetti C, Dematteis A, et al. The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function. Antivir Ther. 2005; 10(2): 215223.
32. De Barros S, Zakaroff-Girard A, Lafontan M, Galitzky J, Bourlier V. Inhibition of human preadipocyte proteasomal activity by HIV protease inhibitors or specific inhibitor lactacystin leads to a defect in adipogenesis, which involves matrix metalloproteinase-9. J Pharmacol Exp Ther. 2007; 320(1): 291-9.
33. Reyskens KM, Essop MF. HIV protease inhibitors and onset of cardiovascular diseases: a central role for oxidative stress and dysregulation of the ubiquitin-proteasome system. Biochim Biophys Acta. 2014; 1842(2): 256-68.
34. Bellera CL, Balcazar DE, Vanrell MC, Casassa AF, Palestro PH, Gavernet L, et al. Computer guided drug repurposing: identification of trypanocidal activity of lofazimine, benidipine and saquinavir. Eur J Med Chem. 2015; 93: 338-48.
35. Sangenito LS, Menna-Barreto RFS, d’Avila-Levy CM, Branquinha MH, Santos ALS. Repositioning of HIV aspartyl peptidase inhibitors for combating the neglected human pathogen Trypanosoma cruzi. Curr Med Chem. 2019; 26(36): 6590-613.
36. Sangenito LS, Menna-Barreto RFS, Oliveira ACS, d’Avila-Levyd CM, Branquinha MH, Santos ALS. Primary evidences of the mechanisms of action of HIV aspartyl peptidase inhibitors on Trypanosoma cruzi trypomastigote forms. Int J Antimicrob Agents. 2018; 52(2): 185-94.
37. Santa-Rita RM, Barbosa HS, de Castro SL. Ultrastructural analysis of edelfosine-treated trypomastigotes and amastigotes of Trypanosoma cruzi. Parasitol Res. 2006; 100(1): 187-90.
38. Díaz-Chiguer DL, Hernández-Luis F, Nogueda-Torres B, Castillo R, Reynoso-Ducoing O, Hernández-Campos A, et al. JVG9, a benzimidazole derivative, alters the surface and cytoskeleton of Trypanosoma cruzi bloodstream trypomastigotes. Mem Inst Oswaldo Cruz. 2014; 109(6): 757-60.
39. Estrada V, Portilla J. Dyslipidemia related to antiretroviral therapy. AIDS Rev. 2011; 13(1): 49-56.
40. Menna-Barreto RF, Salomão K, Dantas AP, Santa-Rita RM, Soares MJ, Barbosa HS, et al. Different cell death pathways induced by drugs in Trypanosoma cruzi: an ultrastructural study. Micron. 200; 40(2): 157-68.
41. Duszenko M, Ginger ML, Brennand A, Gualdrón-López M, Colombo MI, Coombs GH, et al. Autophagy in protists. Autophagy. 2011; 7(2): 127-58.
42. Sangenito LS, d’Avila-Levy CM, Branquinha MH, Santos ALS. Nelfinavir and lopinavir impair Trypanosoma cruzi trypomastigote infection in mammalian host cells and show anti-amastigote activity. Int J Antimicrob Agents. 2016; 48(6): 703-11.
43. Clevenbergh P, Mouly S, Sellier P, Badsi E, Cervoni J, Vincent V, et al. Improving HIV infection management using antiretroviral plasma drug levels monitoring: a clinician’s point of view. Curr HIV Res. 2004; 2(4): 309-21.
44. Estrela RC, Ribeiro FS, Seixas BV, Suarez-Kurtz G. Determination of lopinavir and ritonavir in blood plasma, seminal plasma, saliva and plasma ultra-filtrate by liquid chromatography/tandem mass spectrometry detection. Rapid Commun Mass. Spectrom. 2008; 22(5): 657-64.

Financial support: FAPERJ, CNPq, CAPES (financial code 001).
+ Corresponding author: ibastefano@hotmail.com
ORCID https://orcid.org/0000-0002-3715-1967
Received 08 December 2021
Accepted 14 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

ioc

fiocruz 
faperj cnpq capes