Current and emerging target identification methods for novel antimalarials

Challis, Matthew P.; Devine, Shane M.; Creek, Darren J.

doi:10.1016/j.ijpddr.2022.11.001

Cited by 16 publications

(9 citation statements)

References 101 publications

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“…The main drawback of the phenotypic screens is their agnostic approaches in which, initially, nothing is known about the biological activity of the selected compounds. As such there is an immediate need to study the mechanism of action (MOA) of the compounds to develop these chemical scaffolds into clinically relevant drugs (Challis et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development

Wirjanata

et al. 2021

Preprint

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Despite their widespread use, our understanding of how malaria drugs work remains limited. This includes chloroquine (CQ), the most successful antimalarial ever deployed. Here, we used MS-CETSA and dose-response transcriptional profiling to elucidate protein targets and mechanism of action (MOA) of CQ, as well as MK-4815, a malaria drug candidate with a proposed MOA similar to CQ. We identified falcilysin (FLN) as the target of both compounds and found that hemoglobin digestion was the key biological pathway affected, with distinct MOA profiles between CQ-sensitive and CQ-resistant parasites. We showed that CQ and MK-4815 inhibit FLN proteolytic activity, and using X-ray crystallography, that they occupy a hydrophobic pocket situated within the large peptide substrate binding cavity of FLN. As a key protein in the MOA of CQ, FLN now constitute an interesting target for the development of novel anti-malarial drugs with improved resistance profiles.

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Section: Introductionmentioning

confidence: 99%

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development

Wirjanata

et al. 2021

Preprint

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“…Nonetheless, these data from our SAR scoping of hit compound 2 suggest an alternative prodrug approach for potent but relatively insoluble antimalarial 4(1H)-quinolones 23,24 using their more polar and soluble keto amide 25,26 precursors. Finally, the fairly high potency of this chemotype against T. gondii, but not three other pathogenic protozoa, should help focus downstream mechanistic 27,28 40) 29 (1.4 g, 6.0 mmol) was dissolved in a mixture of DCM (40 mL) and MeOH (10 mL). The mixture was subjected to ozonolysis at −78 °C for 15 min and flushed with oxygen for 5 min.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Antimalarial Dibenzannulated Medium-Ring Keto Lactams

Ren,

Wang,

Leas

et al. 2023

ACS Infect. Dis.

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We discovered dibenzannulated medium-ring keto lactams (11,12-dihydro-5H-dibenzo[b,g]azonine-6,13-diones) as a new antimalarial chemotype. Most of these had chromatographic LogD7.4 values ranging from <0 to 3 and good kinetic solubilities (12.5 to >100 μg/mL at pH 6.5). The more polar compounds in the series (LogD7.4 values of <2) had the best metabolic stability (CLint values of <50 μL/min/mg protein in human liver microsomes). Most of the compounds had relatively low cytotoxicity, with IC50 values >30 μM, and there was no correlation between antiplasmodial activity and cytotoxicity. The four most potent compounds had Plasmodium falciparum IC50 values of 4.2 to 9.4 nM and in vitro selectivity indices of 670 to >12,000. They were more than 4 orders-of-magnitude less potent against three other protozoal pathogens (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, and Leishmania donovani) but did have relatively high potency against Toxoplasma gondii, with IC50 values ranging from 80 to 200 nM. These keto lactams are converted into their poorly soluble 4(1H)-quinolone transannular condensation products in vitro in culture medium and in vivo in mouse blood. The similar antiplasmodial potencies of three keto lactam–quinolone pairs suggest that the quinolones likely contribute to the antimalarial activity of the lactams.

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“…falciparum parasites in culture in large-scale screens. ,, Determining the target of an antimalarial lead compound is often challenging and time-consuming. Current approaches for target identification include in vitro evolution followed by whole genome sequencing, untargeted metabolomics, and proteomic approaches (reviewed in ref ). These approaches are not always successful, and there are several compounds undergoing clinical development for which the modes of action remain unknown (e.g., ref ).…”

Section: Discussionmentioning

confidence: 99%

A pH Fingerprint Assay to Identify Inhibitors of Multiple Validated and Potential Antimalarial Drug Targets

Lindblom,

Zhang,

Lehane

2024

ACS Infect. Dis.

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New drugs with novel modes of action are needed to safeguard malaria treatment. In recent years, millions of compounds have been tested for their ability to inhibit the growth of asexual blood-stage Plasmodium falciparum parasites, resulting in the identification of thousands of compounds with antiplasmodial activity. Determining the mechanisms of action of antiplasmodial compounds informs their further development, but remains challenging. A relatively high proportion of compounds identified as killing asexual blood-stage parasites show evidence of targeting the parasite's plasma membrane Na + -extruding, H +importing pump, PfATP4. Inhibitors of PfATP4 give rise to characteristic changes in the parasite's internal [Na + ] and pH. Here, we designed a "pH fingerprint" assay that robustly identifies PfATP4 inhibitors while simultaneously allowing the detection of (and discrimination between) inhibitors of the lactate:H + transporter PfFNT, which is a validated antimalarial drug target, and the V-type H + ATPase, which was suggested as a possible target of the clinical candidate ZY19489. In our pH fingerprint assays and subsequent secondary assays, ZY19489 did not show evidence for the inhibition of pH regulation by the V-type H + ATPase, suggesting that it has a different mode of action in the parasite. The pH fingerprint assay also has the potential to identify protonophores, inhibitors of the acid-loading Cl − transporter(s) (for which the molecular identity(ies) remain elusive), and compounds that act through inhibition of either the glucose transporter PfHT or glycolysis. The pH fingerprint assay therefore provides an efficient starting point to match a proportion of antiplasmodial compounds with their mechanisms of action.

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Current and emerging target identification methods for novel antimalarials

Cited by 16 publications

References 101 publications

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development

Identification of an inhibitory pocket in falcilysin provides a new avenue for malaria drug development

Antimalarial Dibenzannulated Medium-Ring Keto Lactams

A pH Fingerprint Assay to Identify Inhibitors of Multiple Validated and Potential Antimalarial Drug Targets

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