The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.
A pyridyl-furan series developed from Open Global Health Library blocks red blood cell invasion and protein trafficking in Plasmodium falciparum through potential inhibition of the parasite’s PI4KIIIb enzyme
Open accessPreprint — published as 10.1021/acsinfecdis.3c00138 · Paper page
Abstract
With resistance increasing to current antimalarial medicines, there is an urgent need to discover new drug targets and to develop new medicines against these targets. We therefore screened the Open Global Health Library of Merck KGaA, Darmstadt, Germany of 250 compounds against the asexual blood stage of the deadliest malarial parasite Plasmodium falciparum, from which eight inhibitors with low micromolar potency were found. Due to its combined potencies against parasite growth and inhibition of red blood cell invasion, the pyridyl-furan compound OGHL250, was prioritised for further optimisation. The potency of the series lead compound (WEHI-518) was improved 250-fold to low nanomolar levels against parasite blood-stage growth. Parasites selected for resistance to a related compound MMV396797, were also resistant to WEHI-518 as well as KDU731, an inhibitor of the phosphatidylinositol kinase PfPI4KIIIB, suggesting this kinase is the target of the pyridyl-furan series. Inhibition of PfPI4KIIIB blocks multiple stages of the parasite’s life cycle and other potent inhibitors are currently under preclinical development. MMV396797-resistant parasites possess an E1316D mutation in PfPKI4IIIB which clusters with known resistance mutations of other inhibitors of the kinase. Building upon earlier studies which showed that PfPI4KIIIB inhibitors block the development of the invasive merozoite parasite stage, we show that members of the pyridyl-furan series also block invasion and/or the conversion of merozoites into ring-stage intracellular parasites through inhibition of protein secretion and export into red blood cells.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764
Flagged first, then by citations
Research works printed but not linked: 55
- 10.1056/NEJMoa0808859 · DOI · Paper page
- 10.3201/eid2701.203527 · DOI
- 2021, Increase in the proportion of Plasmodium falciparum with kelch13 C580Y mutation and decline in pfcrt and pfmdr1 mutant alleles in Papua New Guinea, Malar J, 20, 410, 10.1186/s12936-021-03933-6 · DOI
- 2021, Surveillance of molecular markers of Plasmodium falciparum artemisinin resistance (kelch13 mutations) in Papua New Guinea between 2016 and 2018, Int J Parasitol Drugs Drug Resist, 16, 188, 10.1016/j.ijpddr.2021.06.004 · DOI
- Ward, K. E. ; Fidock, D. A. ; Bridgford, J. L. , Plasmodium falciparum resistance to artemisinin-based combination therapies. Curr Opin Microbiol 2022, 69, 102193. · DOI
- 10.1038/nature09107 · DOI
- 10.1038/nature09099 · DOI
- 10.1126/science.1211936 · DOI
- 2021, Prioritization of Molecular Targets for Antimalarial Drug Discovery, ACS Infect Dis, 7, 2764, 10.1021/acsinfecdis.1c00322 · DOI
- 2021, Genomic and Genetic Approaches to Studying Antimalarial Drug Resistance and Plasmodium Biology, Trends Parasitol, 37, 476, 10.1016/j.pt.2021.02.007 · DOI
- 10.1111/mmi.12765 · DOI
- 10.1038/s41598-018-26819-1 · DOI
- 10.1371/journal.ppat.1005763 · DOI
- 10.1016/j.ijpara.2020.01.002 · DOI
- 2018, Targeted Phenotypic Screening in Plasmodium falciparum and Toxoplasma gondii Reveals Novel Modes of Action of Medicines for Malaria Venture Malaria Box Molecules, mSphere, 3, e00534
- Dans, M. ; Piirainen, H. ; Nguyen, W. ; Khurana, S. ; Mehra, S. ; Razook, Z. ; Geoghegan, N. ; Dawson, A. ; Das, S. ; Schneider, M. ; Jonsdottir, T. ; Gabriela, G. ; Gancheva, M. ; Tonkin, C. ; Mollard, V. ; Goodman, C. ; McFadden, G. ; Wilson, D. ; Rogers, K. ; Barry, A. ; Crabb, B. ; de-Koning-Ward, T. ; Sleebs, B. ; Kursula, I. ; Gilson, P. , Sulfonylpiperazine compounds prevent Plasmodium falciparum invasion of red blood cells through interference with actin-1/profilin dynamics. PLoS Biology 2023, 21, e3002066. · DOI
- 10.1016/j.pt.2015.12.007 · DOI
- 10.1371/journal.ppat.1004670 · DOI
- Barnes, C. ; Dans, M. ; Jonsdottir, T. ; Crabb, B. ; Gilson, P. , PfATP4 inhibitors in the Medicines for Malaria Venture Malaria Box and Pathogen Box block the schizont-to-ring transition by inhibiting egress rather than invasion. Frontiers in Cellular and Infection Microbiology 2022. · DOI
- 10.1126/science.1193225 · DOI
- 2022, The Medicines for Malaria Venture Malaria Box contains inhibitors of protein secretion in Plasmodium falciparum blood stage parasites, Traffic, 23, 442, 10.1111/tra.12862 · DOI
- 10.1371/journal.pone.0112571 · DOI
- 10.1371/journal.ppat.1003344 · DOI
- 10.1021/cb501004q · DOI
- 10.1098/rsob.170213 · DOI
- 2019, Targeting malaria parasite invasion of red blood cells as an antimalarial strategy, FEMS Microbiol Rev, 43, 223, 10.1093/femsre/fuz005 · DOI
- 10.1038/ncomms8285 · DOI
- 10.1042/bj3000821 · DOI
- 10.1073/pnas.1306097110 · DOI
- 10.1038/nature22337 · DOI
- Kümpornsin, K. ; Kochakarn, T. ; eo, T. ; Luth, M. ; Pearson, R. ; Hoshizaki, J. ; Mok, S. ; Park, H. ; Uhlemann, A.-C. ; Cubel, S. ; Franco, V. ; Gomez-Lorenzo, M. ; Gamo, F. ; Winzeler, E. ; Fidock, D. ; Chookajorn, T. ; Lee, M. , Generation of a mutator parasite to drive resistome discovery in Plasmodium falciparum . bioRxiv 2022. · DOI
- 2022, A G358S mutation in the Plasmodium falciparum Na(+) pump PfATP4 confers clinically-relevant resistance to cipargamin, Nat Commun, 13, 5746, 10.1038/s41467-022-33403-9 · DOI · Paper page
- 2020, Torin 2 Derivative, NCATS-SM3710, Has Potent Multistage Antimalarial Activity through Inhibition of P. falciparum Phosphatidylinositol 4-Kinase (Pf PI4KIIIbeta), ACS Pharmacol Transl Sci, 3, 948, 10.1021/acsptsci.0c00078 · DOI
- Paquet, T. ; Le Manach, C. ; Cabrera, D. G. ; Younis, Y. ; Henrich, P. P. ; Abraham, T. S. ; Lee, M. C. S. ; Basak, R. ; Ghidelli-Disse, S. ; Lafuente-Monasterio, M. J. ; Bantscheff, M. ; Ruecker, A. ; Blagborough, A. M. ; Zakutansky, S. E. ; Zeeman, A. M. ; White, K. L. ; Shackleford, D. M. ; Mannila, J. ; Morizzi, J. ; Scheurer, C. ; Angulo-Barturen, I. ; Martinez, M. S. ; Ferrer, S. ; Sanz, L. M. ; Gamo, F. J. ; Reader, J. ; Botha, M. ; Dechering, K. J. ; Sauerwein, R. W. ; Tungtaeng, A. ; Vanachayangkul, P. ; Lim, C. S. ; Burrows, J. ; Witty, M. J. ; Marsh, K. C. ; Bodenreider, C. ; Rochford, R. ; Solapure, S. M. ; Jimenez-Diaz, M. B. ; Wittlin, S. ; Charman, S. A. ; Donini, C. ; Campo, B. ; Birkholtz, L. M. ; Hanson, K. K. ; Drewes, G. ; Kocken, C. H. M. ; Delves, M. J. ; Leroy, D. ; Fidock, D. A. ; Waterson, D. ; Street, L. J. ; Chibale, K. , Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase. Sci Transl Med 2017, 9 (387). · DOI
- 10.1038/nature12782 · DOI
- 10.1021/acs.jmedchem.5b00499 · DOI
- Brunschwig, C. ; Lawrence, N. ; Taylor, D. ; Abay, E. ; Njoroge, M. ; Basarab, G. S. ; Le Manach, C. ; Paquet, T. ; Cabrera, D. G. ; Nchinda, A. T. ; de Kock, C. ; Wiesner, L. ; Denti, P. ; Waterson, D. ; Blasco, B. ; Leroy, D. ; Witty, M. J. ; Donini, C. ; Duffy, J. ; Wittlin, S. ; White, K. L. ; Charman, S. A. ; Jimenez-Diaz, M. B. ; Angulo-Barturen, I. ; Herreros, E. ; Gamo, F. J. ; Rochford, R. ; Mancama, D. ; Coetzer, T. L. ; van der Watt, M. E. ; Reader, J. ; Birkholtz, L. M. ; Marsh, K. C. ; Solapure, S. M. ; Burke, J. E. ; McPhail, J. A. ; Vanaerschot, M. ; Fidock, D. A. ; Fish, P. V. ; Siegl, P. ; Smith, D. A. ; Wirjanata, G. ; Noviyanti, R. ; Price, R. N. ; Marfurt, J. ; Silue, K. D. ; Street, L. J. ; Chibale, K. , UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria. Antimicrob Agents Chemother 2018, 62 (9). · DOI
- 10.1093/NAR/GKAB1061 · DOI · Paper page
- 2022, The spleen tyrosine kinase (SYK): A crucial therapeutic target for diverse liver diseases, Heliyon, 8, e12130, 10.1016/j.heliyon.2022.e12130 · DOI
- Solyakov, L. ; Halbert, J. ; Alam, M. M. ; Semblat, J. P. ; Dorin-Semblat, D. ; Reininger, L. ; Bottrill, A. R. ; Mistry, S. ; Abdi, A. ; Fennell, C. ; Holland, Z. ; Demarta, C. ; Bouza, Y. ; Sicard, A. ; Nivez, M. P. ; Eschenlauer, S. ; Lama, T. ; Thomas, D. C. ; Sharma, P. ; Agarwal, S. ; Kern, S. ; Pradel, G. ; Graciotti, M. ; Tobin, A. B. ; Doerig, C. , Global kinomic and phospho-proteomic analyses of the human malaria parasite Plasmodium falciparum. Nat Commun 2011, 2, 565. · DOI
- 2020, A Phase 1, Placebo-controlled, Randomized, Single Ascending Dose Study and a Volunteer Infection Study to Characterize the Safety, Pharmacokinetics, and Antimalarial Activity of the Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048, Clin Infect Dis, 71, e657, 10.1093/cid/ciaa368 · DOI
- Sinxadi, P. ; Donini, C. ; Johnstone, H. ; Langdon, G. ; Wiesner, L. ; Allen, E. ; Duparc, S. ; Chalon, S. ; McCarthy, J. S. ; Lorch, U. ; Chibale, K. ; Mohrle, J. ; Barnes, K. I. , Safety, Tolerability , Pharmacokinetics, and Antimalarial Activity of the Novel Plasmodium Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers. Antimicrob Agents Chemother 2020, 64 (4). · DOI
- 2018, A map of the subcellular distribution of phosphoinositides in the erythrocytic cycle of the malaria parasite Plasmodium falciparum, Int J Parasitol, 48, 13, 10.1016/j.ijpara.2017.08.015 · DOI
- 10.1016/j.ijpara.2008.09.007 · DOI
- 10.1038/nature08104 · DOI
- 2014, Protein export in malaria parasites: an update, Cellular Microbiology, 16, 355, 10.1111/cmi.12261 · DOI
- 10.1016/j.pt.2021.04.009 · DOI
- 10.1074/jbc.M108393200 · DOI
- 10.1073/pnas.94.20.10931 · DOI
- 10.2307/3280287 · DOI
- 10.1111/j.1550-7408.1983.tb02932.x · DOI
- 10.4269/ajtmh.1993.48.205 · DOI
- 2018, Spatial organization of protein export in malaria parasite blood stages, Traffic, 19, 605, 10.1111/tra.12577 · DOI
- 10.1021/cb3002478 · DOI
- 10.1016/j.exppara.2006.09.016 · DOI
Metadata
- Authors
- Ling, D. B., Nguyen, W., Looker, O., Razook, Z., McCann, K., Barry, A. E., Scheurer, C., Wittlin, S., Bullen, H. E., Crabb, B. S., Sleebs, B. E., & Gilson, P. R.
- Affiliations
- Burnet Institute (AU)
- The University of Melbourne (AU)
- Swiss Tropical and Public Health Institute (CH)
- Corresponding author
- Gilson, Paul R.
- ORCID
- Venue
- ACS Infectious Diseases
- Publisher
- openRxiv
- Published
- 2023-04-26
- Volume
- 9
- Issue
- 9
- Pages
- 1695-1710
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC10496428
- OpenAlex
- W4386209303
- Cited by
- 6
- References
- 1
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 2
- FWCI
- 1.54
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- ACS Infectious Diseases (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- Funders
- Burnet Institute
- Merck KGaA
- University of Cape Town
- Medical Research Council
- National Health and Medical Research Council (119780521, 1185354, 2001073)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Phytochemical compounds biological activities
- Physical Sciences › Chemistry › Organic Chemistry › Heterocyclic Compound Synthesis and Bioactivity
- Keywords
- Plasmodium falciparum, phosphatidylinositol kinase, antimalarial drug discovery, erythrocyte invasion, merozoite invasion, protein secretion, protein trafficking, drug resistance, asexual blood stages
- MeSH terms
- Animals, Erythrocytes, Furans, Parasites, Plasmodium falciparum, Global Health, Protein Transport
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
