Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box

Spalenka, Jérémy; Escotte-Binet, Sandie; Bakiri, Ali; Hubert, Jane; Renault, Jean‐Hugues; Velard, Frédéric; Duchateau, Simon; Aubert, Dominique; Huguenin, A; Villena, Isabelle

doi:10.1128/aac.01640-17

Cited by 67 publications

(58 citation statements)

References 40 publications

(56 reference statements)

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“…Furthermore, MMV652003 and MMV688283, which are benzamide 4-quinolinamine class of compounds and predicted to target leucyl-tRNA synthetase and βeta-hematin formation respectively 28–29 , were identified positively as antimalarial hits. Another compound, MMV675968, which has chemical features similar to inhibitors of dihydrofolate reductase (DHFR) in Cryptosporidium and Toxoplasma 8, 11 , displayed potent antimalarial activity with an estimated EC 50 of 0.07 µM. Therefore, it is likely that this compound may be targeting the DHFR enzyme in P. falciparum 30 .…”

Section: Resultsmentioning

confidence: 99%

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Patra

Hingamire

Belekar

et al. 2019

Preprint

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30We report a systematic, cellular phenotype-based antimalarial screening of the MMV Pathogen Box 31 collection, which facilitated the identification of specific blockers of late stage intraerythrocytic 32 Plasmodium falciparum maturation. First, from standard growth inhibition asays, we discovered 62 33 additional antimalarials (EC 50 ≤ 10µM) over previously known antimalarial candidates from Pathogen 34 Box. A total of 90 potent molecules (EC 50 ≤ 1µM) were selected for evaluating their stage-specific 35 effects during the intra-erythrocytic development of P. falciparum. None of these molecules had 36 significant effect on ring-trophozoite transition, 10 molecules inhibited trophozoite-schizont transition, 37 and 21 molecules inhibited schizont-ring transition at 1µM. These compounds were further validated 38 in secondary assays by flow cytometry and microscopic imaging of treated cells to prioritize 12 39 molecules as potent and selective blockers of schizont-ring transition. Seven of these were found to 40 strongly inhibit calcium ionophore induced egress of Toxoplasma gondii, a related apicomplexan 41 parasite, suggesting that the inhibitors may be acting via similar mechanism in the two parasites, 42 which can be further exploited for target identification studies. Two of these molecules, with previously 43 unknown mechanism of action, MMV020670 and MMV026356, were found to induce fragmentation of 44 DNA in developing merozoites. Further mechanistic studies would facilitate therapeutic exploitation of 45 these molecules as broadly active inhibitors targeting development and egress of apicomplexan 46 parasites relevant to human health. 47 48 49 Despite technological advancements and improved knowledge on disease manifestation and 69 pathogen biology, progress in therapeutic development has been slower than expected for human 70 infectious diseases affecting the developing world. In addition to limited financial prospects, 71 pharmaceutical companies remain under significant pressure to address high attrition rates. In this 72 context, repurposing of old drugs is becoming a viable alternative through the exploitation of known 73 compounds with established mechanisms thereby shortening the time window between efficacy 74 testing to pharmacophore optimization 1-3 to eventual application. In recent efforts to speed up the 75 process of drug development against various pathogenic diseases, a collaborative model of public-76 private partnerships (PPPs) facilitated through Medicines for Malaria Venture (MMV: mmv.org) was 77 formed. This resulted in well-characterized drug-like small molecule libraries being made accessible 78 to academics worldwide, for the purpose of identifying novel bioactivities against various tropical 79 disease pathogens and conducting focused mechanistic studies. In 2015, the consortium launched 80 the open access "Pathogen Box" consisting of 400 drug-like small molecules, included 26 reference 81 compounds, with confirmed bioactivity against at least one of the neglected disease pathogens ...

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Section: Resultsmentioning

confidence: 99%

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Patra

Hingamire

Belekar

et al. 2019

Preprint

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“…However, a recent study showed that MMV690102 analogues ineffective against P. falciparum and T. brucei. There is no logical explanation why this compound failed to act as both parasites are known to be inhibited by DHFR inhibitors unless it is explained by the structural divergence between DHFR orthologues expressed in many organisms [21,32,60]. Antileishmanial activity report on the remaining compounds is limited, except the report by MMV on MMV688415 activity against L. infantum amastigotes (IC 50 =17.3 μM) (MMV biological activity data).…”

Section: Activity Of Selected Compounds Against L Donovani Amastigotesmentioning

confidence: 99%

“…Novel antifungal agents were also discovered by Mayer & Kronstad [18]. In addition, PB was also screened for barber's pole worm [19], non-tuberculous mycobacteria species [20], and Toxoplasma gondii [21] resulting in several novel compounds as a starting point for new drug discovery.…”

Section: Introductionmentioning

confidence: 99%

Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

Tadele

Abay

Makonnen

et al. 2019

Preprint

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Leishmaniasis is a collective term used to describe various pathological conditions caused by an obligate intracellular protozoan of the genus Leishmania. It is one of the neglected diseases and has been given low attention in drug discovery researches to narrow the existing gap in safety and efficacy of the currently used drugs to treat leishmaniasis. The challenge is further exacerbated by the emergence of drug resistance by the parasites. Aiming to look for potential anti-leishmanial hits and leads, we screened MMV Pathogen Box against clinically isolated L. donovani strain. Compounds were screened against promastigote, and then against amastigote stages; of which, 35 compounds showed >50% inhibition on promastigotes in the initial screen (1 μM). Out of these compounds, 9 compounds showed >70% inhibition with median inhibitory concentration (IC 50 ) ranges from 12 nM to 491 nM on anti-promastigote assay and 53 to 704 nM on intracellular amastigote assay. Identified compounds demonstrated good safety on THP-1 cell lines and sheep RBCs, and appropriate physico-chemical property suitable for further drug development. Two compounds (MMV690102 and MMV688262) were identified as lead compounds. Among these compounds, anti-tubercular agent MMV688262 (delamanid) showed synergistic effect with amphotericin B, indicating the prospect of this compound for combination therapy. The current study indicates the presence of additional hits which may hold promise as starting points for anti-leishmanial drug discovery and in-depth structure activity relationship studies. Future works also needs to investigate antiamastigotes activity of remaining 'hits', which were not covered in the present study. | P a g e Authors summaryVisceral leishmaniasis is a major public health problem in endemic regions. Different drugs have been used to treat visceral leishmaniasis. However, the available drugs are either toxic, noncompliance to the patient, painful upon administration, low in efficacy, or costly. New chemical entities that overcome the limitations of existing drugs are therefore desperately needed.Screening of 400 pathogen box compounds against of Leishmania donovani clinical isolate resulted in identification of 35 compounds with >50% inhibition against promastigotes at 1 μM.Out of these compounds, 9 showed >70% inhibition with median inhibitory concentration ranges from 12 nM to 491 nM on anti-promastigote assay, and 53 to 704 nM on intracellular amastigote assay. Our work identified new compounds which hold promise for further drug development.

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“…T. gondii is an obligate cosmopolitan apicomplexan intracellular parasite which affects more than one‐third of the world population . Infection by T. gondii causes the worldwide disease toxoplasmosis .…”

Section: Introductionmentioning

confidence: 99%

“…A few numbers of medications available for the treatment of toxoplasmosis show several limitations, including drug intolerance, low bioavailability, high toxicity, and drug resistance developed by the parasite. Thus, there is critical need to design novel compounds able to inhibit parasite invasion or proliferation with high selectivity, potency, and minimum toxicity for the human host . Heterocycles containing pyrimidine moiety have significant roles in medicinal chemistry.…”

Section: Introductionmentioning

confidence: 99%

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

Hariri

Ghasemi

Shirini

et al. 2018

Journal of Chemometrics

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Dihydrofolate reductase (DHFR) is an essential enzyme in the folate metabolism pathway and an important target of antineoplastic, antimicrobial, antiprotozoal, and antiinflammatory drugs. Despite the clinical effectiveness of current antifolate treatments, new drugs are needed to be designed due to developing resistance of this enzyme through multiple‐site mutagenesis. Understanding the factors affecting the ligand binding selectivity profiles among DHFR families is critical for the design of novel potent and selective inhibitors, with the least side effects, against DHFR of pathogens. Hybrid scaffolds containing pyrimidine ring are effective in DHFR inhibition. In this study, using proteochemometric (PCM) modeling, we designed and evaluated new potent pyrimidine scaffold‐based inhibitors via 3‐dimensional alignment‐free GRid‐INdependent Descriptors (GRIND), VolSurf molecular, and sequence‐based (z‐scale) descriptors to provide ligand and receptor descriptors, respectively. Validation and robustness of the model were confirmed by venetian blinds cross‐validation and Y‐scrambling approaches, respectively. Applicability domain (AD) analysis was performed to estimate the likelihood of reliable prediction for compounds. To show the applicability of the PCM model, new ligands were designed using structural data retrieved from this model. Inhibitory activities of the designs were then predicted, and selectivity ratio profiles were investigated. Finally, potent and highly selective inhibitors were identified regarding the protozoan parasite Toxoplasma gondii, followed by evaluating the ADMET parameters of the ligands.

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Discovery of New Inhibitors of Toxoplasma gondii via the Pathogen Box

Cited by 67 publications

References 40 publications

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Whole Cell Phenotypic Screening Of MMV Pathogen Box identifies Specific Inhibitors of Plasmodium falciparum merozoite maturation and egress

Identification of Leishmania donovani inhibitors from pathogen box compounds of Medicine for Malaria Venture

Probing the origin of dihydrofolate reductase inhibition via proteochemometric modeling

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