A Review of Recent Patents on the Protozoan Parasite HSP90 as a Drug Target

Angel, Sérgio O.; Matrajt, Mariana; Echeverria, Pablo Christian

doi:10.2174/1872208311307010002

Cited by 20 publications

(18 citation statements)

References 46 publications

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“…In recent years, research has focused on the development of new drugs against T. gondii [10-12]. Nevertheless, the need to identify and evaluate new drugs based on new and innovative therapeutic strategies against T. gondii is still evident.…”

Section: Resultsmentioning

confidence: 99%

“…The nifurtimox-resistant Trypanosoma cruzi LQ strain has shown a greater sensitivity to βCs, most likely due to inhibition of the respiratory chain of the parasite [26]. The chaperone HSP90 is an important drug target in protozoan parasites and new drugs are actively being sought [12,27]. In this regard, harmine was one of the three compounds selected among approximately 4,000 small molecules that inhibited P. falciparum HSP90 by specific competition with its ATP-binding domain.…”

Section: Resultsmentioning

confidence: 99%

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In vitro evaluation of β-carboline alkaloids as potential anti-Toxoplasma agents

et al. 2013

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BackgroundToxoplasmosis is a worldwide infection caused by the protozoan parasite Toxoplasma gondii, which causes chorioretinitis and neurological defects in congenitally infected newborns or immunodeficient patients. The efficacy of the current treatment is limited, primarily by serious host toxicity. In recent years, research has focused on the development of new drugs against T. gondii. β-Carbolines (βCs), such as harmane, norharmane and harmine, are a group of naturally occurring alkaloids that show microbicidal activity. In this work, harmane, norharmane and harmine were tested against T. gondii.FindingsThe treatment of extracellular tachyzoites with harmane, norharmane and harmine showed a 2.5 to 3.5-fold decrease in the invasion rates at doses of 40 μM (harmane and harmine) and 2.5 μM (norharmane) compared with the untreated parasites. Furthermore, an effect on the replication rate could also be observed with a decrease of 1 (harmane) and 2 (norharmane and harmine) division rounds at doses of 5 to 12.5 μM. In addition, the treated parasites presented either delayed or no monolayer lysis compared with the untreated parasites.ConclusionsThe three βC alkaloids studied (norharmane, harmane and harmine) exhibit anti-T. gondii effects as evidenced by the partial inhibition of parasite invasion and replication. A dose–response effect was observed at a relatively low drug concentration (< 40 μM), at which no cytotoxic effect was observed on the host cell line (Vero).

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In vitro evaluation of β-carboline alkaloids as potential anti-Toxoplasma agents

et al. 2013

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“…Because of this, the identification and characterization of essential or specific proteins which may be participating in essential cellular processes in T. gondii pathogenesis would allow the generation of novel therapies. The parasite chaperone Hsp90 is an interesting drug target against acute and latent toxoplasmosis (Angel et al 2013). …”

Section: Discussionmentioning

confidence: 99%

“…It is expected that specific proteins of the parasite, which play important or essential roles in T. gondii pathogenesis, allow the generation of novel therapies that can overcome some of the afore-mentioned situations. In this regard, the chaperone heat shock protein 90 (Hsp90) has arisen as an interesting drug target against acute and latent toxoplasmosis (Shonhai et al 2011; Angel et al 2013; Roy et al 2012; Rochani et al 2013). …”

Section: Toxoplasma Gondii and Toxoplasmosismentioning

confidence: 99%

Toxoplasma gondiiHsp90: potential roles in essential cellular processes of the parasite

et al. 2014

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SUMMARY Hsp90 is a widely distributed and highly conserved molecular chaperone that is ubiquitously expressed throughout nature, being one of the most abundant proteins within non-stressed cells. This chaperone is up-regulated following stressful events and has been involved in many cellular processes. In Toxoplasma gondii, Hsp90 could be linked with many essential processes of the parasite such as host cell invasion, replication and tachyzoite-bradyzoite interconversion. A Protein-Protein Interaction (PPI) network approach of TgHsp90 has allowed inferring how these processes may be altered. In addition, data mining of T. gondii phosphoproteome and acetylome has allowed the generation of the phosphorylation and acetylation map of TgHsp90. This review focuses on the potential roles of TgHsp90 in parasite biology and the analysis of experimental data in comparison with its counterparts in yeast and humans.

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“…Accordingly, there is an urgent need to evaluate new drugs based on novel and innovative therapeutic strategies against T. gondii that are both efficacious and nontoxic for humans (Rodriguez and Szajnman, 2012; Vanagas et al, 2012; Angel et al, 2013). Therefore, the goal of the present systematic review was to retrieve published studies related to in vitro and in vivo evaluation of drugs and compounds for the treatment of toxoplasmosis (2006–2016) in order to prepare comprehensive data for designing more accurate investigations in future.…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

et al. 2017

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The currently available anti-Toxoplasma agents have serious limitations. This systematic review was performed to evaluate drugs and new compounds used for the treatment of toxoplasmosis. Data was systematically collected from published papers on the efficacy of drugs/compounds used against Toxoplasma gondii (T. gondii) globally during 2006–2016. The searched databases were PubMed, Google Scholar, Science Direct, ISI Web of Science, EBSCO, and Scopus. One hundred and eighteen papers were eligible for inclusion in this systematic review, which were both in vitro and in vivo studies. Within this review, 80 clinically available drugs and a large number of new compounds with more than 39 mechanisms of action were evaluated. Interestingly, many of the drugs/compounds evaluated against T. gondii act on the apicoplast. Therefore, the apicoplast represents as a potential drug target for new chemotherapy. Based on the current findings, 49 drugs/compounds demonstrated in vitro half-maximal inhibitory concentration (IC50) values of below 1 μM, but most of them were not evaluated further for in vivo effectiveness. However, the derivatives of the ciprofloxacin, endochin-like quinolones and 1-[4-(4-nitrophenoxy) phenyl] propane-1-one (NPPP) were significantly active against T. gondii tachyzoites both in vitro and in vivo. Thus, these compounds are promising candidates for future studies. Also, compound 32 (T. gondii calcium-dependent protein kinase 1 inhibitor), endochin-like quinolones, miltefosine, rolipram abolish, and guanabenz can be repurposed into an effective anti-parasitic with a unique ability to reduce brain tissue cysts (88.7, 88, 78, 74, and 69%, respectively). Additionally, no promising drugs are available for congenital toxoplasmosis. In conclusion, as current chemotherapy against toxoplasmosis is still not satisfactory, development of well-tolerated and safe specific immunoprophylaxis in relaxing the need of dependence on chemotherapeutics is a highly valuable goal for global disease control. However, with the increasing number of high-risk individuals, and absence of a proper vaccine, continued efforts are necessary for the development of novel treatment options against T. gondii. Some of the novel compounds reviewed here may represent good starting points for the discovery of effective new drugs. In further, bioinformatic and in silico studies are needed in order to identify new potential toxoplasmicidal drugs.

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A Review of Recent Patents on the Protozoan Parasite HSP90 as a Drug Target

Cited by 20 publications

References 46 publications

In vitro evaluation of β-carboline alkaloids as potential anti-Toxoplasma agents

In vitro evaluation of β-carboline alkaloids as potential anti-Toxoplasma agents

Toxoplasma gondiiHsp90: potential roles in essential cellular processes of the parasite

A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006–2016)

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