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. 2022 Mar 16:117:e210386.
doi: 10.1590/0074-02760210386. eCollection 2022.

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

Leandro Stefano Sangenito  1 , Claudia Masini d'Avila-Levy  2 , Marta Helena Branquinha  1 , André Luis Souza Dos Santos  1   3
Affiliations

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

Leandro Stefano Sangenito et al. Mem Inst Oswaldo Cruz. .

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.

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Figures

Fig. 1:
Fig. 1:. chemical structures of the human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) that presenting relevant anti-Trypanosoma cruzi activity.
Fig. 2:
Fig. 2:. effects of human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) on the morphology and on the ultrastructure of Trypanosoma cruzi trypomastigotes Y strain. (Panel A) Giemsa-stained smears of trypomastigotes treated for 4 h with HIV-PIs at concentrations ranging from 1 to 50 µM. The treatment with the HIV-PIs induce numerous morphological changes, such as parasites becoming round in shape with reduced cell size (arrowhead), swollen of cell body (black thin arrow), and shortening or loss of flagellum (white arrow). Note: All HIV-PIs induce such changes. The images are a representative set of the treatment with then. (Panel B) Scanning electron microscopy images of trypomastigotes treated with the LD50 dose of nelfinavir (8.6 µM) or lopinavir (10.6 µM) show parasites displaying flagellum shortening (a, thin arrow), body retraction (a and e, arrowhead), ruffling (b, star) and blebs (d, asterisk) of the plasma membrane and atypical body torsion in the posterior end of the cell body (c and e, large arrow). Adapted from Sangenito and coworkers.
Fig. 3:
Fig. 3:. bright field microscopy of the susceptibility of Trypanosoma cruzi intracellular amastigotes to the treatment with the human immunodeficiency virus aspartyl peptidase inhibitors (HIV-PIs) nelfinavir and lopinavir in LLC-MK2 cells and RAW macrophages. The host cells were previously infected with trypomastigotes for 24 h at 37ºC and then treated daily or not (control) with nelfinavir and lopinavir for 48 h (RAW macrophages) and 72 h (LLC-MK2 cells). Finally, the association index was determined by counting 200 cells in each of duplicated coverslips. The arrowheads point to the intracellular parasites. Adapted from Sangenito and coworkers.
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