Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out

Dechering, Koen J.; Timmerman, Martijn; Rensen, Kim; Koolen, Karin M. J.; Honarnejad, Saman; Vos, Martijn; Huijs, Tonnie; Henderson, Rob; Chenu, Elodie; Laleu, Benoît; Montefiore, Bailey C.; Segall, Matthew D.; Mills, James E.; Guantai, Eric M.; Duffy, James; Duffey, Maëlle

doi:10.1016/j.slasd.2022.07.002

Cited by 9 publications

(13 citation statements)

References 28 publications

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“…2f). Given the relatively low infection rate of NF54 parasites, we evaluated the recently described NF175 strain that is, like NF54, of West-African origin and shows drug susceptibility identical to NF54 23,24 . In agreement with published data, sporozoites from strain NF175 gave on average higher infection rates than those of strain NF54 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening

et al. 2023

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The sporozoite stages of malaria parasites are the primary cause of infection of the vertebrate host and are targeted by (experimental) vaccines. Yet, little is known about their susceptibility to chemical intervention. Phenotypic high-throughput screens have not been feasible due to a lack of in vitro systems. Here we tested 78 marketed and experimental antimalarial compounds in miniaturized assays addressing sporozoite viability, gliding motility, hepatocyte traversal, and intrahepatocytic schizogony. None potently interfered with sporozoite viability or motility but ten compounds acted at the level of schizogony with IC50s < 100 nM. To identify compounds directly targeting sporozoites, we screened 81,000 compounds from the Global Health Diversity and reFRAME libraries in a sporozoite viability assay using a parasite expressing a luciferase reporter driven by the circumsporozoite promoter. The ionophore gramicidin emerged as the single hit from this screening campaign. Its effect on sporozoite viability translated into reduced gliding motility and an inability of sporozoites to invade human primary hepatocytes and develop into hepatic schizonts. While providing proof of concept for a small molecule sporontocidal mode of action, our combined data indicate that liver schizogony is more accessible to chemical intervention by (candidate) antimalarials.

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Section: Resultsmentioning

confidence: 99%

Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening

et al. 2023

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“…A recent report describes the use of this screening cascade to screen 141 786 compounds from which 33 antimalarial molecules with a robust data package and potential for further development ("Confirmed Actives") were identified. 22 Here, this state of the art screening platform was applied to CQL (Figure 3). During solubilization and reformatting activities, 40 samples were identified with solubility issues and removed from the screening set, thereby leaving 5810 compounds (4623 scored + 1187 randomly selected).…”

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confidence: 99%

“…A recent report describes the use of this screening cascade to screen 141 786 compounds from which 33 antimalarial molecules with a robust data package and potential for further development ("Confirmed Actives") were identified. 22 The results of this screening have been published in ChEMBL. 23 Here, this state of the art screening platform was applied to CQL (Figure 3).…”

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confidence: 99%

“…22 The results of this screening have been published in ChEMBL. 23 Here, this state of the art screening platform was applied to CQL (Figure 3). During solubilization and reformatting activities, 40 samples were identified with solubility issues and removed from the screening set, thereby leaving 5810 compounds (4623 scored + 1187 randomly selected).…”

mentioning

confidence: 99%

“…The high-throughput screening (HTS) cascade contains orthogonal efficacy and cytotoxicity assays. A recent report describes the use of this screening cascade to screen 141 786 compounds from which 33 antimalarial molecules with a robust data package and potential for further development (“Confirmed Actives”) were identified . The results of this screening have been published in ChEMBL …”

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MAIP: An Open-Source Tool to Enrich High-Throughput Screening Output and Identify Novel, Druglike Molecules with Antimalarial Activity

Bosc,

Felix,

Gardner

et al. 2023

ACS Med. Chem. Lett.

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Efforts to tackle malaria must continue for a disease that threatens half of the global population. Parasite resistance to current therapies requires new chemotypes that are able to demonstrate effectiveness and safety. Previously, we developed a machine-learning-based approach to predict compound antimalarial activity, which was trained on the compound collections of several organizations. The resulting prediction platform, MAIP, was made freely available to the scientific community and offers a solution to prioritize molecules of interest in virtual screening and hit-to-lead optimization. Here, we experimentally validate MAIP and demonstrate how the approach was used in combination with a robust compound selection workflow and a recently introduced innovative high-throughput screening (HTS) cascade to select and purchase compounds from a public library for subsequent experimental screening. We observed a 12-fold enrichment compared with a randomly selected set of molecules, and the eight hits we ultimately selected exhibit good potency and absorption, distribution, metabolism, and excretion (ADME) profiles.

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Leveraging off higher plant phylogenetic insights for antiplasmodial drug discovery

Moyo,

Invernizzi,

Mianda

et al. 2023

Nat. Prod. Bioprospect.

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The antimalarial drug-resistance conundrum which threatens to reverse the great strides taken to curb the malaria scourge warrants an urgent need to find novel chemical scaffolds to serve as templates for the development of new antimalarial drugs. Plants represent a viable alternative source for the discovery of unique potential antiplasmodial chemical scaffolds. To expedite the discovery of new antiplasmodial compounds from plants, the aim of this study was to use phylogenetic analysis to identify higher plant orders and families that can be rationally prioritised for antimalarial drug discovery. We queried the PubMed database for publications documenting antiplasmodial properties of natural compounds isolated from higher plants. Thereafter, we manually collated compounds reported along with plant species of origin and relevant pharmacological data. We systematically assigned antiplasmodial-associated plant species into recognised families and orders, and then computed the resistance index, selectivity index and physicochemical properties of the compounds from each taxonomic group. Correlating the generated phylogenetic trees and the biological data of each clade allowed for the identification of 3 ‘hot’ plant orders and families. The top 3 ranked plant orders were the (i) Caryophyllales, (ii) Buxales, and (iii) Chloranthales. The top 3 ranked plant families were the (i) Ancistrocladaceae, (ii) Simaroubaceae, and (iii) Buxaceae. The highly active natural compounds (IC50 ≤ 1 µM) isolated from these plant orders and families are structurally unique to the ‘legacy’ antimalarial drugs. Our study was able to identify the most prolific taxa at order and family rank that we propose be prioritised in the search for potent, safe and drug-like antimalarial molecules.

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Replenishing the malaria drug discovery pipeline: Screening and hit evaluation of the MMV Hit Generation Library 1 (HGL1) against asexual blood stage Plasmodium falciparum, using a nano luciferase reporter read-out

Cited by 9 publications

References 28 publications

Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening

Assessment of the drugability of initial malaria infection through miniaturized sporozoite assays and high-throughput screening

MAIP: An Open-Source Tool to Enrich High-Throughput Screening Output and Identify Novel, Druglike Molecules with Antimalarial Activity

Leveraging off higher plant phylogenetic insights for antiplasmodial drug discovery

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