Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

Boss, Christoph; Aissaoui, Hamed; Amaral, Nathalie; Bauer, Aude; Bazire, Stephanie; Binkert, Christoph A.; Brun, Reto; Bürki, Cédric; Ciana, Claire-Lise; Corminboeuf, Olivier; Delahaye, Stéphane; Dollinger, Claire; Fischli, Christoph; Fischli, Walter; Flock, Alexandre; Frantz, Marie‐Céline; Girault, Malory; Grisostomi, Corinna; Friedli, Astrid; Heidmann, Bibia; Hinder, Claire; Jacob, Gaël; Bihan, Amélie Le; Malrieu, Sophie; Mamzed, Saskia; Merot, Aurelien; Meyer, Solange; Peixoto, Sabrina; Petit, Nolwenn; Siegrist, Romain; Trollux, Julien; Weller, Thomas; Wittlin, Sergio

doi:10.1002/cmdc.201600298

Cited by 23 publications

(19 citation statements)

References 44 publications

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“…Although some of these nonsynonymous changes could have been maintained within the population by chance, some are plausible targets of selection. For example, although resistance to ACT-451840 is conferred by mutations in pfmdr1 ( 61 ), a mutation was observed in the gene encoding a putative replication factor C subunit 4 (PF3D7_1241700) that results in a S42T amino acid change near the ATP-binding pocket in two independent ACT-451840–resistant clones ( 61 ). Replication factor C subunit 4 is the subunit ATPase in the clamp-loading DNA polymerase complex, is likely essential, and is a good drug target.…”

Section: Discussionmentioning

confidence: 99%

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Cowell

Istvan

Lukens

et al. 2018

Science

223

242

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Chemogenetic characterization through in vitro evolution combined with whole-genome analysis can identify antimalarial drug targets and drug-resistance genes. We performed a genome analysis of 262 Plasmodium falciparum parasites resistant to 37 diverse compounds. We found 159 gene amplifications and 148 nonsynonymous changes in 83 genes associated with drug-resistance acquisition, where gene amplifications contributed to one-third of resistance acquisition events. Beyond confirming previously identified multidrug-resistance mechanisms, we discovered hitherto unrecognized drug target–inhibitor pairs, including thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This exploration of the P. falciparum resistome and druggable genome will likely guide drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms available to the malaria parasite.

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Section: Discussionmentioning

confidence: 99%

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Cowell

Istvan

Lukens

et al. 2018

Science

223

242

View full text Add to dashboard Cite

show abstract

“…Although some of these nonsynonymous changes could have arisen by chance, some are plausible. For example, although resistance to ACT-451840 is known to be conferred by mutations in pfmdr1 (62), a mutation in the gene encoding a putative replication factor C subunit 4 (PF3D7_1241700) that results in a S42T amino acid change near the ATP binding pocket was found in two independent ACT-451840-resistant clones(62) ( Figure S6). Replication factor C subunit 4 is the subunit ATPase in the clamp-loading DNA polymerase complex and would be expected to be essential and a good drug target.…”

Section: Discussionmentioning

confidence: 99%

Mapping the malaria parasite drug-able genome usingin vitroevolution and chemogenomics

Cowell

Istvan²,

Lukens

et al. 2017

Preprint

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Chemogenetic characterization through in vitro evolution combined with whole genome analysis is a powerful tool to discover novel antimalarial drug targets and identify drug resistance genes. Our comprehensive genome analysis of 262 Plasmodium falciparum parasites treated with 37 diverse compounds reveals how the parasite evolves to evade the action of small molecule growth inhibitors. This detailed data set revealed 159 gene amplifications and 148 nonsynonymous changes in 83 genes which developed during resistance acquisition. Using a new algorithm, we show that gene amplifications contribute to 1/3 of drug resistance acquisition events. In addition to confirming known multidrug resistance mechanisms, we discovered novel multidrug resistance genes. Furthermore, we identified promising new drug target-inhibitor pairs to advance the malaria elimination campaign, including: thymidylate synthase and a benzoquinazolinone, farnesyltransferase and a pyrimidinedione, and a dipeptidylpeptidase and an arylurea. This deep exploration of the P. falciparum resistome and drug-able genome will guide future drug discovery and structural biology efforts, while also advancing our understanding of resistance mechanisms of the deadliest malaria parasite.One Sentence Summary: Whole genome sequencing reveals how Plasmodium falciparum evolves resistance to diverse compounds and identifies new antimalarial drug targets.peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/139386 doi: bioRxiv preprint first posted online 3 Main Text:Malaria has a disproportionately negative impact on human health because its causal protozoan parasites are adept at changing their genomes to evade antimalarial drugs and the human immune system. A human infection may contain upwards of to 10 12 asexual blood stage parasites.Thus, even with a relatively slow random parasite mutation rate (~10 -9 ), within a few cycles of replication each base in the P. falciparum genome can acquire a random genetic change that may render at least one parasite resistant to the activity of a small molecule or a human-encoded antibody. The recent evolution of artemisinin-resistant parasites in Southeast Asia now threatens a life-saving treatment in addition to malaria control efforts(1).Although this rapid evolution impedes our ability to control the disease, it can also be used to our advantage since in vitro evolution in the presence of known antimalarials followed by whole-genome sequencing of resistant clones can be used to discover important mediators of drug resistance. For example, the kelch13 allele that is associated with artemisinin resistance was first identified in the genome sequence of an in vitro cultured P. falciparum parasite line exposed to sublethal concentrations of dihydroartemisinin in the laboratory(2). This method of resistance evolution can also reveal new antimalarial drug targets(3). Unlike drug targets that are val...

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“…ACT‐451840, a preclinical drug molecule, is another example of a compound with potent activity against sensitive and resistant P. falciparum strains (Fig. ) . Preclinical studies of CT‐451840 have been carried out by several groups in partnership with academic and industrial researchers .…”

Section: Chemical Compounds Effective Against Various Life Stagesmentioning

confidence: 99%

“…6). [70][71][72] Preclinical studies of CT-451840 have been carried out by several groups in partnership with academic and industrial researchers. 73 This compound exhibited a range of activities against multiple life cycle stages of the human malaria parasite P. falciparum (asexual and sexual) and P. vivax (asexual).…”

Section: Pipeline Drug Candidatesmentioning

confidence: 99%

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

Poonam

Gupta

et al. 2018

Medicinal Research Reviews

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Over time, several exciting advances have been made in the treatment and prevention of malaria; however, this devastating disease continues to be a major global health problem and affects millions of people every year. Notably, the paucity of new efficient drug molecules and the inevitable drug resistance of the malaria parasite, Plasmodium falciparum, against frontline therapeutics are the foremost struggles facing malaria eradication initiatives. According to the malaria eradication agenda, the discovery of new chemical entities that can destroy the parasite at the liver stage, the asexual blood stage, the gametocyte stage, and the insect ookinete stage of the parasite life cycle (i.e., compounds exhibiting multistage activity) are in high demand, preferably with novel and multiple modes of action. Phenotypic screening of chemical libraries against the malaria parasite is certainly a crucial step toward overcoming these crises. In the last few years, various research groups, including industrial research laboratories, have performed large-scale phenotypic screenings that have identified a wealth of chemical entities active against multiple life stages of the malaria parasite. Vital scientific and technological developments have led to the discovery of multistage inhibitors of the malaria parasite; these compounds, considered highly valuable starting points for subsequent drug discovery and eradication of malaria, are reviewed.

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Discovery and Characterization of ACT‐451840: an Antimalarial Drug with a Novel Mechanism of Action

Cited by 23 publications

References 44 publications

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Mapping the malaria parasite druggable genome by using in vitro evolution and chemogenomics

Mapping the malaria parasite drug-able genome usingin vitroevolution and chemogenomics

Multistage inhibitors of the malaria parasite: Emerging hope for chemoprotection and malaria eradication

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