Antiretroviral activity of protease inhibitors against Toxoplasma gondii

Monzote, Lianet; Rodríguez, Marta; Alfonso, Yenisey; Cox, Raymundo

doi:10.1590/s0036-46652013000100012

Cited by 9 publications

(3 citation statements)

References 14 publications

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“…falciparum [ 70 ], Leishmania [ 71 ] and T . gondii [ 72 , 73 ]. In addition a native Kunitz-type serine protease inhibitor was recently proven to affect viability of T .…”

Section: Discussionmentioning

confidence: 99%

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

et al. 2015

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Regulated proteolysis is known to control a variety of vital processes in apicomplexan parasites including invasion and egress of host cells. Serine proteases have been proposed as targets for drug development based upon inhibitor studies that show parasite attenuation and transmission blockage. Genetic studies suggest that serine proteases, such as subtilisin and rhomboid proteases, are essential but functional studies have proved challenging as active proteases are difficult to express. Proteinaceous Protease Inhibitors (PPIs) provide an alternative way to address the role of serine proteases in apicomplexan biology. To validate such an approach, a Neospora caninum Kazal inhibitor (NcPI-S) was expressed ectopically in two apicomplexan species, Toxoplasma gondii tachyzoites and Plasmodium berghei ookinetes, with the aim to disrupt proteolytic processes taking place within the secretory pathway. NcPI-S negatively affected proliferation of Toxoplasma tachyzoites, while it had no effect on invasion and egress. Expression of the inhibitor in P. berghei zygotes blocked their development into mature and invasive ookinetes. Moreover, ultra-structural studies indicated that expression of NcPI-S interfered with normal formation of micronemes, which was also confirmed by the lack of expression of the micronemal protein SOAP in these parasites. Our results suggest that NcPI-S could be a useful tool to investigate the function of proteases in processes fundamental for parasite survival, contributing to the effort to identify targets for parasite attenuation and transmission blockage.

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“…falciparum [ 70 ], Leishmania [ 71 ] and T . gondii [ 72 , 73 ]. In addition a native Kunitz-type serine protease inhibitor was recently proven to affect viability of T .…”

Section: Discussionmentioning

confidence: 99%

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

et al. 2015

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“…Therefore, in the present investigation, we screened one FDA library comprising 666 small-molecule compounds to identify those that inhibited T. gondii growth. Although we used a known anti-Toxoplasma agent, pyrimethamine, to serve as a positive control, we also noticed that the library contained some established anti-Toxoplasma compounds, such as atazanavir [41], cyclosporine and PHA665752 [28], that, as expected, significantly inhibited T. gondii growth. On the other hand, we found that several compounds, such as SB-408124, semaxanib and U0126, had no effect on T. gondii growth, which is consistent with previous findings [28].…”

Section: Discussionmentioning

confidence: 57%

“…Of the five compounds with the highest inhibitory efficiency (≥ 90% parasite inhibition), three have been reported to inhibit the growth of T. gondii [28,41]. Thus, the remaining two compounds, NVP-AEW541 and GSK-J4 HCl, were further analysed at various concentrations to verify their antiparasitic activity and to determine their therapeutic index (TI).…”

Section: Validation Of the Antiparasitic Activity Of Nvp-aew541 And G...mentioning

confidence: 99%

Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain

Liu

Hua

et al. 2020

Parasites Vectors

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Background Toxoplasma gondii is a zoonotic pathogen that causes toxoplasmosis and leads to serious public health problems in developing countries. However, current clinical therapeutic drugs have some disadvantages, such as serious side effects, a long course of treatment and the emergence of drug-resistant strains. The urgent need to identify novel anti-Toxoplasma drugs has initiated the effective strategy of repurposing well-characterized drugs. As a principled screening for the identification of effective compounds against Toxoplasma gondii, in the current study, a collection of 666 compounds were screened for their ability to significantly inhibit Toxoplasma growth. Methods The inhibition of parasite growth was determined using a luminescence-based β-galactosidase activity assay. Meanwhile, the effect of compounds on the viability of host cells was measured using CCK8. To assess the inhibition of the selected compounds on discrete steps of the T. gondii lytic cycle, the invasion, intracellular proliferation and egress abilities were evaluated. Finally, a murine infection model of toxoplasmosis was used to monitor the protective efficacy of drugs against acute infection of a highly virulent RH strain. Results A total of 68 compounds demonstrated more than 70% parasite growth inhibition. After excluding compounds that impaired host cell viability, we further characterized two compounds, NVP-AEW541 and GSK-J4 HCl, which had IC50 values for parasite growth of 1.17 μM and 2.37 μM, respectively. In addition, both compounds showed low toxicity to the host cell. Furthermore, we demonstrated that NVP-AEW541 inhibits tachyzoite invasion, while GSK-J4 HCl inhibits intracellular tachyzoite proliferation by halting cell cycle progression from G1 to S phase. These findings prompted us to analyse the efficacy of the two compounds in vivo by using established mouse models of acute toxoplasmosis. In addition to prolonging the survival time of mice acutely infected with T. gondii, both compounds had a remarkable ability to reduce the parasite burden of tissues. Conclusions Our findings suggest that both NVP-AEW541 and GSK-J4 could be potentially repurposed as candidate drugs against T. gondii infection.

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Treatment with melatonin induces a reduction of Toxoplasma gondii development in LLC-MK2 cells

et al. 2020

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Antiretroviral activity of protease inhibitors against Toxoplasma gondii

Cited by 9 publications

References 14 publications

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

Ectopic Expression of a Neospora caninum Kazal Type Inhibitor Triggers Developmental Defects in Toxoplasma and Plasmodium

Two old drugs, NVP-AEW541 and GSK-J4, repurposed against the Toxoplasma gondii RH strain

Treatment with melatonin induces a reduction of Toxoplasma gondii development in LLC-MK2 cells

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