Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis

Dennis, Adelaide S. M.; Rosling, James E. O.; Lehane, Adele M.; Kirk, Kiaran

doi:10.1038/s41598-018-26819-1

Cited by 40 publications

(88 citation statements)

References 25 publications

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“…Similarly, MMV020710 ( 585 ) and MMV020520 ( 586 ), and MMV020623 ( 587 ), MMV020136 ( 588 ), MMV085210 ( 589 ), and MMV01059 ( 590 ) were found to disrupt Na + homeostasis, through an ATPase‐associated phenotype …”

Section: Malariamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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The Pathogen Box is a 400‐strong collection of drug‐like compounds, selected for their potential against several of the world's most important neglected tropical diseases, including trypanosomiasis, leishmaniasis, cryptosporidiosis, toxoplasmosis, filariasis, schistosomiasis, dengue virus and trichuriasis, in addition to malaria and tuberculosis. This library represents an ensemble of numerous successful drug discovery programmes from around the globe, aimed at providing a powerful resource to stimulate open source drug discovery for diseases threatening the most vulnerable communities in the world. This review seeks to provide an in‐depth analysis of the literature pertaining to the compounds in the Pathogen Box, including structure–activity relationship highlights, mechanisms of action, related compounds with reported activity against different diseases, and, where appropriate, discussion on the known and putative targets of compounds, thereby providing context and increasing the accessibility of the Pathogen Box to the drug discovery community.

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Section: Malariamentioning

confidence: 99%

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Veale

2019

ChemMedChem

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“…As a consequence, multiple events such as swelling of the parasite (8,10), changes in the lipid composition of the parasite plasma membrane (PPM) and premature schizogony (11), and eryptosis (7) seem to contribute to parasite demise. Interestingly, 7-9% of the collection of antimalarial compounds included in the Malaria and the Pathogen Boxes distributed by Medicines for Malaria Venture (MMV) appear to inhibit PfATP4 as judged by their ability to cause Na + influx into the parasite and disruption of lipid homeostasis within the PPM (12)(13)(14). Resistance to several of these compounds has been shown to be associated with mutations in PfATP4 (5,7,8,15,16).…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Oligomerization of the antimalarial drug targetPfATP4 is essential for parasite survival

Ramanathan

Morrisey

Daly

et al. 2019

Preprint

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Plasmodium falciparum P-type ATPase (PfATP4) is a Na + efflux pump crucial for maintaining low [Na + ] i in malaria parasites during their intraerythrocytic development cycle. In recent years, multiple studies have shown PfATP4 to be the target of a large number of chemical scaffolds, including current candidate antimalarials KAE609 and SJ733. Here we show that PfATP4 exists as a large complex. Immunopurification and proteomic studies revealed the complex to be homooligomeric in nature. The complex appears to be assembled cotranslationally. Phylogenetic analysis suggests that ATP4 from apicomplexans and chromerids form a distinct class of P-type ATPases having fewer transmembrane helices compared to their orthologues. We hypothesized that reduction of transmembrane helices in PfATP4 might necessitate oligomerization to maintain its function. We further suspected potential involvement of π-π interactions between aromatic amino acids within the terminal transmembrane helix of each monomer to be critical for oligomerization. To test this hypothesis, we mutated three aromatic amino acids in the last transmembrane helix of PfATP4. Wildtype and the mutated PfATP4 genes were introduced at an ectopic locus in a P. falciparum line, in which endogenous PfATP4 was conditionally expressed. Whereas the wildtype copy of PfATP4 expressed from the ectopic locus was able to form the oligomeric complex, the mutant PfATP4 failed to do so. Strikingly, unlike the wildtype, the mutant PfATP4 failed to functionally complement the knockdown of the endogenous gene, leading to parasite demise.These results strongly suggest that co-translational oligomerization of PfATP4 is essential for its function and for parasite survival. Significance StatementPlasmodium falciparum ATP4 (PfATP4) is a Na + efflux pump and is the target of at least two antimalarial drug candidates (KAE609, SJ733) currently in clinical trials. With a rapid parasite clearance rate (t 99 =12h) in initial clinical studies, PfATP4-active drugs present the prospect of taking us a step closer to 3 malaria elimination in a world that is currently threatened by artemisinin resistance. In this study, we have established that PfATP4 exists as a homooligomeric complex, which is assembled co-translationally through interactions facilitated by aromatic amino acids in its last transmembrane helix. Crucially, its existence as a complex is essential for its function. This exposes a vulnerability in the target that could be potentially exploited for drug design.

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“…MMV020623, MMV020520, MMV020081, MMV020710 and MMV020391, which are reported to target PfATP4 and disrupt cellular cation homeostasis, were also found to strongly inhibit [S→R] transition suggesting that PfATP4 activity maybe important for parasite egress 45–46 . MMV024443 (an indole-2-carboxamide) which has been shown to target P. falciparum calcium-dependent protein kinase 1 ( Pf CDPK1) 47–49 showed excellent egress inhibition in our studies.…”

Section: Resultsmentioning

confidence: 98%

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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Diverse antimalarials from whole-cell phenotypic screens disrupt malaria parasite ion and volume homeostasis

Cited by 40 publications

References 25 publications

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

Unpacking the Pathogen Box—An Open Source Tool for Fighting Neglected Tropical Disease

WITHDRAWN: Oligomerization of the antimalarial drug targetPfATP4 is essential for parasite survival

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

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