Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials

Watt, Mariëtte van der; Reader, Janette; Churchyard, Alisje; Nondaba, Sindisiwe; Lauterbach, Sonja; Niemand, Jandeli; Abayomi, Sijuade; Biljon, Riëtte van; Connacher, Jessica; Wyk, Roelof van; Manach, Claire Le; Paquet, Tanya; Cabrera, Diego Gonzàlez; Brunschwig, Christel; Theron, Anjo; Lozano-Arias, Sonia; Rodrigues, Janneth; Herreros, Esperanza; Leroy, Didier; Duffy, James; Street, Leslie J.; Chibale, Kelly; Mancama, D; Coetzer, Thérèsa L.; Birkholtz, Lyn‐Marié

doi:10.1093/jac/dky008

Cited by 19 publications

(56 citation statements)

References 55 publications

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“…The diaminoquinazoline chemotype has been shown to be particularly effective HKMTi against asexual P. falciparum parasites, with screens of diversity sets identifying selective inhibitors 15,30 . Although these data support the notion that epigenetic modulators could be drug targets in parasite development as well as differentiation, some chemotypes show overt toxicity, poor selectivity and sometimes poor pharmacokinetics 31 . Diverse chemotypes targeting various epigenetic modulators should therefore be explored.…”

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confidence: 64%

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Coetzee

Grüning

Opperman

et al. 2020

Sci Rep

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The epigenome of the malaria parasite, Plasmodium falciparum, is associated with regulation of various essential processes in the parasite including control of proliferation during asexual development as well as control of sexual differentiation. The unusual nature of the epigenome has prompted investigations into the potential to target epigenetic modulators with novel chemotypes. Here, we explored the diversity within a library of 95 compounds, active against various epigenetic modifiers in cancerous cells, for activity against multiple stages of P. falciparum development. We show that P. falciparum is differentially susceptible to epigenetic perturbation during both asexual and sexual development, with early stage gametocytes particularly sensitive to epi-drugs targeting both histone and nonhistone epigenetic modifiers. Moreover, 5 compounds targeting histone acetylation and methylation show potent multistage activity against asexual parasites, early and late stage gametocytes, with transmission-blocking potential. Overall, these results warrant further examination of the potential antimalarial properties of these hit compounds. The almost inevitable development of drug resistance in malaria parasites enforces continued discovery of novel classes of antimalarial compounds 1. To contribute to global malaria elimination strategies, such compounds would need to target multiple life cycle stages of the parasite 2. This includes targeting the rapidly dividing (~48 h) asexual parasites to reduce parasite burden, as well as targeting mature, terminally differentiated sexual gametocytes to block onward human-to-mosquito transmission of the parasite, or exo-erythrocytic liver stage development to block mosquito-to-human transmission. Importantly, to prolong or prevent resistance development, new chemical matter should target novel biological activities in the parasite 3. In oncology research, epigenetic therapeutics ('epi-drugs') evidently hold great promise as targets for anticancer therapies 4 , with several drugs approved for clinical use, including Azacitidine, Decitabine, Vorinostat and Romidepsin 5. The antitumor activity is ascribed to epigenetic deregulation as a result of inhibition of epigenetic modulators, including histone modifying enzymes and DNA methyltransferases. This results in particular changes in histone post-translational modifications (PTMs), disruption of transcriptional processes, chromatin structure maintenance and DNA repair 6,7. Plasmodium falciparum relies heavily on epigenetic mechanisms to drive both asexual proliferation and sexual differentiation (reviewed in 8-11). The parasite's genome encodes a unique complement of histone modifying enzymes including histone deacetylases (HDACs), histone acetyltransferases (HATs), histone methyltransferases (HMTs, including lysine HKMT), protein arginine methyltransferases (PRMTs), and histone demethylases (HDMs) 12 in addition to other non-histone epigenetic modifiers. As a result, inhibitors of histone modifying enzymes have been investigated as no...

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confidence: 64%

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Coetzee

Grüning

Opperman

et al. 2020

Sci Rep

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“…had identified a series of related imidzopyridazines (e.g., 471 ) as inhibitors of Pf PI4K, suggesting that the compounds identified by Chibale and co‐workers inhibited a common biological pathway. Both classes of compounds in addition to the diaminothienopyrimidines (which are discussed below) were found to inhibit asexual parasites and gametocytes . The Pathogen Box features two imidzopyridazine analogues (MMV010545, 472 and MMV023985, 473 ) with structural features closely resembling several reported antiplasmodial imidzopyridazines, the antiplasmodial activity of which remains unreported.…”

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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“…Lastly, to interrogate the sensitivity and multifaceted use of the biomarker transcripts, they were further evaluated in their usefulness to classify the MoA of new compounds, without the use of our trained ML model. Two compounds that are closely related to the PI4K kinase inhibitors MMV’048 and UCT’943 were included: MMV666810 and MMV675850 ( van der Watt et al., 2018 ) with transcriptome data obtained from GEO with accession code GSE167068 (van Biljon et al submitted to this special issue). These compounds were used to treat immature gametocytes, and this allowed an additional dimensionality in our analysis to include stage-specific variability between asexual parasites and immature gametocytes.…”

Section: Methodsmentioning

confidence: 99%

“…Conserved Plasmodium protein, unknown function DFMO (van Brummelen et al, 2008) Ornithine decarboxylase pf3D7_0503400 Actin-depolymerizing factor 1 pf3D7_0509100…”

Section: Treatmentmentioning

confidence: 99%

“…Although P. falciparum relies on tight control of gene expression to regulate various processes during its complex life cycle ( Bozdech et al., 2003 ; van Biljon et al., 2019 ), reproducible, specific and unique chemically-induced changes in gene expression patterns can be elicited. Asexual blood stage parasites treated with compounds with different MoAs show distinct and divergent transcriptomic responses ( Hu et al., 2009 ; Siwo et al., 2015 ; van der Watt et al., 2018 ). This has also been observed for immature gametocytes ( Ngwa et al., 2017 ; Ngwa et al., 2019 ; Reader et al., 2021 ), which implies that chemically-induced transcriptome responses can be detected for various life cycle stages of the parasite.…”

Section: Introductionmentioning

confidence: 99%

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Machine Learning Uses Chemo-Transcriptomic Profiles to Stratify Antimalarial Compounds With Similar Mode of Action

Heerden

Wyk

Birkholtz

2021

Front. Cell. Infect. Microbiol.

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The rapid development of antimalarial resistance motivates the continued search for novel compounds with a mode of action (MoA) different to current antimalarials. Phenotypic screening has delivered thousands of promising hit compounds without prior knowledge of the compounds’ exact target or MoA. Whilst the latter is not initially required to progress a compound in a medicinal chemistry program, identifying the MoA early can accelerate hit prioritization, hit-to-lead optimization and preclinical combination studies in malaria research. The effects of drug treatment on a cell can be observed on systems level in changes in the transcriptome, proteome and metabolome. Machine learning (ML) algorithms are powerful tools able to deconvolute such complex chemically-induced transcriptional signatures to identify pathways on which a compound act and in this manner provide an indication of the MoA of a compound. In this study, we assessed different ML approaches for their ability to stratify antimalarial compounds based on varied chemically-induced transcriptional responses. We developed a rational gene selection approach that could identify predictive features for MoA to train and generate ML models. The best performing model could stratify compounds with similar MoA with a classification accuracy of 76.6 ± 6.4%. Moreover, only a limited set of 50 biomarkers was required to stratify compounds with similar MoA and define chemo-transcriptomic fingerprints for each compound. These fingerprints were unique for each compound and compounds with similar targets/MoA clustered together. The ML model was specific and sensitive enough to group new compounds into MoAs associated with their predicted target and was robust enough to be extended to also generate chemo-transcriptomic fingerprints for additional life cycle stages like immature gametocytes. This work therefore contributes a new strategy to rapidly, specifically and sensitively indicate the MoA of compounds based on chemo-transcriptomic fingerprints and holds promise to accelerate antimalarial drug discovery programs.

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Potent Plasmodium falciparum gametocytocidal compounds identified by exploring the kinase inhibitor chemical space for dual active antimalarials

Abstract: This study encompasses an in-depth evaluation of the kinase inhibitor space for gametocytocidal activity. Potent lead compounds have enticing dual activities and highlight the importance of targeting the kinase superfamily in malaria elimination strategies.

Cited by 19 publications

References 55 publications

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

Epigenetic inhibitors target multiple stages of Plasmodium falciparum parasites

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

Machine Learning Uses Chemo-Transcriptomic Profiles to Stratify Antimalarial Compounds With Similar Mode of Action

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