Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment

Aguilera, Elena; Varela, Javier; Serna, Elva; Torres, Susana; Yaluff, Gloria; Bilbao, Ninfa Vera de; Cerecetto, Hugo; Álvarez, Guzmán; González, Mercedes

doi:10.1590/0074-02760170267

Cited by 12 publications

(6 citation statements)

References 30 publications

(53 reference statements)

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“…Associations with benznidazole have not always represented a promising alternative, showing antagonism or only an additive effect among the drugs tested [ 56 – 58 ]. Although some combinations with benznidazole have shown good results in in vitro assays [ 55 , 59 , 60 ], few have led to clinical studies and also with unsatisfactory results [ 41 , 52 ]. These data could justify our choice of compounds for combination tests excluding benznidazole, as already reported in the literature [ 61 – 63 ].…”

Section: Discussionmentioning

confidence: 99%

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

et al. 2021

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Butanolides have shown a variety of biological effects including anti-inflammatory, antibacterial, and antiprotozoal effects against certain strains of Trypanosoma cruzi. Considering the lack of an effective drug to treat T. cruzi infections and the prominent results obtained in literature with this class of lactones, we investigated the anti-T. cruzi activity of five butanolides isolated from two species of Lauraceae, Aiouea trinervis and Mezilaurus crassiramea. Initially, the activity of these compounds was evaluated on epimastigote forms of the parasite, after a treatment period of 4 h, followed by testing on amastigotes, trypomastigotes, and mammalian cells. Next, the synergistic effect of active butanolides against amastigotes was evaluated. Further, metacyclogenesis inhibition and infectivity assays were performed for the most active compound, followed by ultrastructural analysis of the treated amastigotes and trypomastigotes. Among the five butanolides studied, majoranolide and isoobtusilactone A were active against all forms of the parasite, with good selectivity indexes in Vero cells. Both butanolides were more active than the control drug against trypomastigote and epimastigote forms and also had a synergic effect on amastigotes. The most active compound, isoobtusilactone A, which showed activity against all tested strains inhibited metacyclogenesis and infection of new host cells. In addition, ultrastructural analysis revealed that this butanolide caused extensive damage to the mitochondria of both amastigotes and trypomastigotes, resulting in severe morphological changes in the infective forms of the parasite. Altogether, our results highlight the potential of butanolides against the etiologic agent of Chagas disease and the relevance of isoobtusilactone A as a strong anti-T. cruzi drug, affecting different events of the life cycle and all evolutionary forms of parasite after a short period of exposure.

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Section: Discussionmentioning

confidence: 99%

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

et al. 2021

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“…[ 8–12 ] Also, some works have proposed a selective target, such as the enzyme triosephosphate isomerase (TIM) [ 13 ] ; this glycolytic enzyme has been used as a therapeutic target for the development of new drugs against various pathogenic organisms, such as Trypanosoma cruzi , Trypanosoma brucei , E. histolytica , Giardia duodenalis , Trichomonas vaginalis , Clostridium perfringens , among others. [ 14–24 ] In addition, other researchers are looking for the repositioning of commercial drugs as antiparasitics. [ 25,26 ] The triosephosphate isomerase of E. histolytica (EhTIM) [ 27 ] has an identity of 41.33% with human TIM (HsTIM); this difference in amino acids favors the development of new drugs with a selective target against EhTIM.…”

Section: Introductionmentioning

confidence: 99%

Amoebicidal effect of 5,5′‐[(4‐nitrophenyl)methylene]bis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone), a new drug against Entamoeba histolytica

Vique‐Sánchez¹,

Jiménez-Pineda

Benítez‐Cardoza

2020

Archiv der Pharmazie

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Entamoeba histolytica is a cosmopolitan protozoan parasite that can produce infections in the intestine and some organs (liver, lungs, and brain), with worldwide prevalence. There are treatments against E. histolytica (antiparasitics), but as the drugs used in these treatments have presented some type of resistance and/or side effects, there are cases with complications of this disease. Therefore, it is necessary to develop new drugs aimed at a specific therapeutic target against this parasite. Here, we used the compound 5,5′‐[(4‐nitrophenyl)methylene]bis(6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone) in the patenting process (called D4). D4 has a reported specific use against a glycolytic enzyme, the triosephosphate isomerase of Trichomonas vaginalis (TvTIM). We determined that D4 has an amoebicidal effect in in vitro cultures, with an IC50 value of 18.5 µM, and we proposed a specific site of interaction (Lys77, His110, Gln115, and Glu118) in the triosephosphate isomerase of E. histolytica (EhTIM). Furthermore, compound D4 has favorable experimental and theoretical toxicity results. Therefore, D4 should be further investigated as a potential drug against E. histolytica.

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“…Experimental toxicity studies with both drugs evidenced neurotoxicity, testicular damage, ovarian toxicity, and deleterious effects in the adrenal, colon, esophageal, and mammary tissue as well as significant mutagenic effects [12]. Despite recent efforts to discover new treatments for Chagas disease, such as drug combinations, drug repositioning, redosing schemes for current drugs, and identifying new drugs with specified target profiles or additive or synergistic interactions of compounds with different modes of actions, better safety and greater effectiveness of drug treatment is not yet available [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

Arce-Fonseca

Carbajal-Hernández

Lozano-Camacho

et al. 2020

Journal of Immunology Research

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Chagas disease is a chronic and potentially lethal disorder caused by the parasite Trypanosoma cruzi, and an effective treatment has not been developed for chronic Chagas disease. The objective of this study was to determine the effectiveness of a therapeutic DNA vaccine containing T. cruzi genes in dogs with experimentally induced Chagas disease through clinical, pathological, and immunological analyses. Infection of Beagle dogs with the H8 T. cruzi strain was performed intraperitoneally with 3500 metacyclic trypomastigotes/kg body weight. Two weeks after infection, plasmid DNA immunotherapy was administered thrice at 15-day intervals. The clinical (physical and cabinet studies), immunological (antibody and cytokine profiles and lymphoproliferation), and macro- and microscopic pathological findings were described. A significant increase in IgG and cell proliferation was recorded after immunotherapy, and the highest stimulation index (3.02) was observed in dogs treated with the pBCSSP4 plasmid. The second treatment with both plasmids induced an increase in IL-1, and the third treatment with the pBCSSP4 plasmid induced an increase in IL-6. The pBCSP plasmid had a good Th1 response regulated by high levels of IFN-gamma and TNF-alpha, whereas the combination of the two plasmids did not have a synergistic effect. Electrocardiographic studies registered lower abnormalities and the lowest number of individuals with abnormalities in each group treated with the therapeutic vaccine. Echocardiograms showed that the pBCSSP4 plasmid immunotherapy preserved cardiac structure and function to a greater extent and prevented cardiomegaly. The two plasmids alone controlled the infection moderately by a reduction in the inflammatory infiltrates in heart tissue. The immunotherapy was able to reduce the magnitude of cardiac lesions and modulate the cellular immune response; the pBCSP treatment showed a clear Th1 response; and pBCSSP4 induced a balanced Th1/Th2 immune response that prevented severe cardiac involvement. The pBCSSP4 plasmid had a better effect on most of the parameters evaluated in this study; therefore, this plasmid can be considered an optional treatment against Chagas disease in naturally infected dogs.

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Looking for combination of benznidazole and Trypanosoma cruzi-triosephosphate isomerase inhibitors for Chagas disease treatment

Cited by 12 publications

References 30 publications

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

Synergistic effect and ultrastructural changes in Trypanosoma cruzi caused by isoobtusilactone A in short exposure of time

Amoebicidal effect of 5,5′‐[(4‐nitrophenyl)methylene]bis‐6‐hydroxy‐2‐mercapto‐3‐methyl‐4(3H)‐pyrimidinone), a new drug against Entamoeba histolytica

DNA Vaccine Treatment in Dogs Experimentally Infected with Trypanosoma cruzi

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