ORCID Profile
0000-0002-0050-9101
Current Organisations
Universiti Malaya
,
Australian National University
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Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1038/S41598-021-86204-3
Abstract: Toxoplasma gondii and Plasmodium falciparum parasites both extrude l -lactate, a byproduct of glycolysis. The P. falciparum Formate Nitrite Transporter, Pf FNT, mediates l -lactate transport across the plasma membrane of P. falciparum parasites and has been validated as a drug target. The T. gondii genome encodes three FNTs that have been shown to transport l -lactate, and which are proposed to be the targets of several inhibitors of T. gondii proliferation. Here, we show that each of the Tg FNTs localize to the T. gondii plasma membrane and are capable of transporting l -lactate across it, with Tg FNT1 making the primary contribution to l -lactate transport during the disease-causing lytic cycle of the parasite. We use the Xenopus oocyte expression system to provide direct measurements of l -lactate transport via Tg FNT1. We undertake a genetic analysis of the importance of the tgfnt genes for parasite proliferation, and demonstrate that all three tgfnt genes can be disrupted in idually and together without affecting the lytic cycle under in vitro culture conditions. Together, our experiments identify the major lactate transporter in the disease causing stage of T. gondii , and reveal that this transporter is not required for parasite proliferation, indicating that Tg FNTs are unlikely to be targets for anti- Toxoplasma drugs.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2018
DOI: 10.1038/S41598-018-26819-1
Abstract: Four hundred structurally erse drug-like compounds comprising the Medicines for Malaria Venture’s ‘Pathogen Box’ were screened for their effect on a range of physiological parameters in asexual blood-stage malaria ( Plasmodium falciparum ) parasites. Eleven of these compounds were found to perturb parasite Na + , pH and volume in a manner consistent with inhibition of the putative Na + efflux P-type ATPase PfATP4. All eleven compounds fell within the subset of 125 compounds included in the Pathogen Box on the basis of their having been identified as potent inhibitors of the growth of asexual blood-stage P . falciparum parasites. All eleven compounds inhibited the Na + -dependent ATPase activity of parasite membranes and showed reduced efficacy against parasites carrying mutations in PfATP4. This study increases the number of chemically erse structures known to show a ‘PfATP4-associated’ phenotype, and adds to emerging evidence that a high proportion (7–9%) of the structurally erse antimalarial compounds identified in whole cell phenotypic screens share the same mechanism of action, exerting their antimalarial effect via an interaction with PfATP4.
Publisher: Wiley
Date: 25-04-2022
DOI: 10.1111/ODI.14206
Abstract: To describe the development of a platform for image collection and annotation that resulted in a multi-sourced international image dataset of oral lesions to facilitate the development of automated lesion classification algorithms. We developed a web-interface, hosted on a web server to collect oral lesions images from international partners. Further, we developed a customised annotation tool, also a web-interface for systematic annotation of images to build a rich clinically labelled dataset. We evaluated the sensitivities comparing referral decisions through the annotation process with the clinical diagnosis of the lesions. The image repository hosts 2474 images of oral lesions consisting of oral cancer, oral potentially malignant disorders and other oral lesions that were collected through MeMoSA This is the first description of a database with clinically labelled oral lesions. This database could accelerate the improvement of AI algorithms that can promote the early detection of high-risk oral lesions.
Publisher: Elsevier BV
Date: 11-2012
Publisher: Elsevier BV
Date: 03-2017
Publisher: Portland Press Ltd.
Date: 10-12-2014
DOI: 10.1042/BJ20131007
Abstract: As it grows and replicates within the erythrocytes of its host the malaria parasite takes up nutrients from the extracellular medium, exports metabolites and maintains a tight control over its internal ionic composition. These functions are achieved via membrane transport proteins, integral membrane proteins that mediate the passage of solutes across the various membranes that separate the biochemical machinery of the parasite from the extracellular environment. Proteins of this type play a key role in antimalarial drug resistance, as well as being candidate drug targets in their own right. This review provides an overview of recent work on the membrane transport biology of the malaria parasite-infected erythrocyte, encompassing both the parasite-induced changes in the membrane transport properties of the host erythrocyte and the cell physiology of the intracellular parasite itself.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.CHEMBIOL.2018.06.009
Abstract: Malaria is a serious threat to human health and additional classes of antimalarial drugs are greatly needed. The human defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity but also undesirable chemokine properties. We engineered a peptide containing the isolated PF4 antiplasmodial domain, which through cyclization, retained the critical structure of the parent protein. The peptide, cPF4PD, killed cultured blood-stage Plasmodium falciparum with low micromolar potency by specific disruption of the parasite digestive vacuole. Its mechanism of action involved selective penetration and accumulation inside the intraerythrocytic parasite without damaging the host cell or parasite membranes it did not accumulate in uninfected cells. This selective activity was accounted for by observations of the peptide's specific binding and penetration of membranes with exposed negatively charged phospholipid headgroups. Our findings highlight the tremendous potential of the cPF4PD scaffold for developing antimalarial peptide drugs with a distinct and selective mechanism of action.
Publisher: American Chemical Society (ACS)
Date: 06-11-2020
DOI: 10.26434/CHEMRXIV.13194755.V1
Abstract: The discovery of new antimalarial medicines with novel mechanisms of action is key to combating the problem of increasing resistance to our frontline treatments. The Open Source Malaria (OSM) consortium has been developing compounds ("Series 4") that have potent activity against Plasmodium falciparum in vitro and in vivo and that have been suggested to act through the inhibition of Pf ATP4, an essential membrane ion pump that regulates the parasite’s intracellular Na + concentration. The structure of Pf ATP4 is yet to be determined. In the absence of structural information about this target, a public competition was created to develop a model that would allow the prediction of anti- Pf ATP4 activity among Series 4 compounds, thereby reducing project costs associated with the unnecessary synthesis of inactive compounds.In the first round, in 2016, six participants used the open data collated by OSM to develop moderately predictive models using erse methods. Notably, all submitted models were available to all other participants in real time. Since then further bioactivity data have been acquired and machine learning methods have rapidly developed, so a second round of the competition was undertaken, in 2019, again with freely-donated models that other participants could see. The best-performing models from this second round were used to predict novel inhibitory molecules, of which several were synthesised and evaluated against the parasite. One such compound, containing a motif that the human chemists familiar with this series would have dismissed as ill-advised, was active. The project demonstrated the abilities of new machine learning methods in the prediction of active compounds where there is no biological target structure, frequently the central problem in phenotypic drug discovery. Since all data and participant interactions remain in the public domain, this research project “lives” and may be improved by others.
Publisher: Springer Science and Business Media LLC
Date: 18-05-2016
DOI: 10.1038/NCOMMS11553
Abstract: Antimalarial chemotherapy, globally reliant on artemisinin-based combination therapies (ACTs), is threatened by the spread of drug resistance in Plasmodium falciparum parasites. Here we use zinc-finger nucleases to genetically modify the multidrug resistance-1 transporter PfMDR1 at amino acids 86 and 184, and demonstrate that the widely prevalent N86Y mutation augments resistance to the ACT partner drug amodiaquine and the former first-line agent chloroquine. In contrast, N86Y increases parasite susceptibility to the partner drugs lumefantrine and mefloquine, and the active artemisinin metabolite dihydroartemisinin. The PfMDR1 N86 plus Y184F isoform moderately reduces piperaquine potency in strains expressing an Asian/African variant of the chloroquine resistance transporter PfCRT. Mutations in both digestive vacuole-resident transporters are thought to differentially regulate ACT drug interactions with host haem, a product of parasite-mediated haemoglobin degradation. Global mapping of these mutations illustrates where the different ACTs could be selectively deployed to optimize treatment based on regional differences in PfMDR1 haplotypes.
Publisher: Oxford University Press (OUP)
Date: 19-06-2017
DOI: 10.1093/JXB/ERX188
Publisher: Elsevier BV
Date: 04-2019
Publisher: Springer Basel
Date: 2011
Publisher: Springer Science and Business Media LLC
Date: 16-05-2010
Publisher: Proceedings of the National Academy of Sciences
Date: 12-2014
Abstract: Useful antimalarial drugs must be rapidly acting, highly efficacious, and have low potential for developing resistance. (+)-SJ733 targets a Plasmodium cation-transporting ATPase, ATP4. (+)-SJ733 cleared parasites in vivo as quickly as artesunate by specifically inducing eryptosis/senescence in infected, treated erythrocytes. Although in vitro selection of pfatp4 mutants with (+)-SJ733 proceeded with moderate frequency, during in vivo selection of pbatp4 mutants, resistance emerged slowly and produced marginally resistant mutants with poor fitness. In addition, (+)-SJ733 met all other criteria for a clinical candidate, including high oral bioavailability, a high safety margin, and transmission blocking activity. These results demonstrate that targeting ATP4 has great potential to deliver useful drugs for malaria eradication.
Publisher: Public Library of Science (PLoS)
Date: 28-07-2016
Publisher: Elsevier BV
Date: 08-2007
Publisher: Springer Science and Business Media LLC
Date: 2008
Publisher: Public Library of Science (PLoS)
Date: 21-07-2016
Publisher: Wiley
Date: 20-05-2015
DOI: 10.1111/MMI.13035
Publisher: Institute of Electrical and Electronics Engineers (IEEE)
Date: 2020
Publisher: Elsevier BV
Date: 12-2012
Publisher: CSIRO Publishing
Date: 2011
DOI: 10.1071/FP09189
Abstract: Present work focussed on improving the description of organogenesis, morphogenesis and metabolism in a biophysical plant model (SUNFLO) applied to sunflower (Helianthus annuus L.). This first version of the model is designed for potential growth conditions without any abiotic or biotic stresses. A greenhouse experiment was conducted to identify and estimate the phenotypic traits involved in plant productivity variability of 26 sunflower genotypes. The ability of SUNFLO to discriminate the genotypes was tested on previous results of a field survey aimed at evaluating the genetic progress since 1960. Plants were phenotyped in four directions phenology, architecture, photosynthesis and biomass allocation. Twelve genotypic parameters were chosen to account for the phenotypic variability. SUNFLO was built to evaluate their respective contribution to the variability of yield potential. A large phenotypic variability was found for all genotypic parameters. SUNFLO was able to account for 80% of observed variability in yield potential and to analyse the phenotypic variability of complex plant traits such as light interception efficiency or seed yield. It suggested that several ways are possible to reach high yields in sunflower. Unlike classical statistical analysis, this modelling approach highlights some efficient parameter combinations used by the most productive genotypes. The next steps will be to evaluate the genetic determinisms of the genotypic parameters.
Publisher: Elsevier BV
Date: 07-2004
Publisher: Springer Science and Business Media LLC
Date: 31-03-2015
DOI: 10.1038/NCOMMS7721
Abstract: The intraerythrocytic malaria parasite relies primarily on glycolysis to fuel its rapid growth and reproduction. The major byproduct of this metabolism, lactic acid, is extruded into the external medium. In this study, we show that the human malaria parasite Plasmodium falciparum expresses at its surface a member of the microbial formate-nitrite transporter family (PfFNT), which, when expressed in Xenopus laevis oocytes, transports both formate and lactate. The transport characteristics of PfFNT in oocytes (pH-dependence, inhibitor-sensitivity and kinetics) are similar to those of the transport of lactate and formate across the plasma membrane of mature asexual-stage P. falciparum trophozoites, consistent with PfFNT playing a major role in the efflux of lactate and hence in the energy metabolism of the intraerythrocytic parasite.
Publisher: Oxford University Press (OUP)
Date: 26-10-2015
Abstract: It is becoming increasingly apparent that certain mutations in the Plasmodium falciparum chloroquine resistance transporter (PfCRT) alter the parasite's susceptibility to erse compounds. Here we investigated the interaction of PfCRT with 3 tricyclic compounds that have been used to treat malaria (quinacrine [QC] and methylene blue [MB]) or to study P. falciparum (acridine orange [AO]). We measured the antiplasmodial activities of QC, MB, and AO against chloroquine-resistant and chloroquine-sensitive P. falciparum and determined whether QC and AO affect the accumulation and activity of chloroquine in these parasites. We also assessed the ability of mutant (PfCRT(Dd2)) and wild-type (PfCRT(D10)) variants of the protein to transport QC, MB, and AO when expressed at the surface of Xenopus laevis oocytes. Chloroquine resistance-conferring isoforms of PfCRT reduced the susceptibility of the parasite to QC, MB, and AO. In chloroquine-resistant (but not chloroquine-sensitive) parasites, AO and QC increased the parasite's accumulation of, and susceptibility to, chloroquine. All 3 compounds were shown to bind to PfCRT(Dd2), and the transport of QC and MB via this protein was saturable and inhibited by the chloroquine resistance-reverser verapamil. Our findings reveal that the PfCRT(Dd2)-mediated transport of tricyclic antimalarials reduces the parasite's susceptibility to these drugs.
Publisher: Wiley
Date: 04-06-2014
DOI: 10.1111/JIPB.12198
Abstract: This work evaluates the phenotypic response of the model grass (Brachypodium distachyon (L.) P. Beauv.) to nitrogen and phosphorus nutrition using a combination of imaging techniques and destructive harvest of shoots and roots. Reference line Bd21-3 was grown in pots using 11 phosphorus and 11 nitrogen concentrations to establish a dose-response curve. Shoot biovolume and biomass, root length and biomass, and tissue phosphorus and nitrogen concentrations increased with nutrient concentration. Shoot biovolume, estimated by imaging, was highly correlated with dry weight (R(2) > 0.92) and both biovolume and growth rate responded strongly to nutrient availability. Higher nutrient supply increased nodal root length more than other root types. Photochemical efficiency was strongly reduced by low phosphorus concentrations as early as 1 week after germination, suggesting that this measurement may be suitable for high throughput screening of phosphorus response. In contrast, nitrogen concentration had little effect on photochemical efficiency. Changes in biovolume over time were used to compare growth rates of four accessions in response to nitrogen and phosphorus supply. We demonstrate that a time series image-based approach coupled with mathematical modeling provides higher resolution of genotypic response to nutrient supply than traditional destructive techniques and shows promise for high throughput screening and determination of genomic regions associated with superior nutrient use efficiency.
Publisher: American Society for Microbiology
Date: 06-2018
DOI: 10.1128/AAC.00087-18
Abstract: For an increasing number of antimalarial agents identified in high-throughput phenotypic screens, there is evidence that they target PfATP4, a putative Na + efflux transporter on the plasma membrane of the human malaria parasite Plasmodium falciparum . For several such “PfATP4-associated” compounds, it has been noted that their addition to parasitized erythrocytes results in cell swelling. Here we show that six structurally erse PfATP4-associated compounds, including the clinical candidate KAE609 (cipargamin), induce swelling of both isolated blood-stage parasites and intact parasitized erythrocytes. The swelling of isolated parasites is dependent on the presence of Na + in the external environment and may be attributed to the osmotic consequences of Na + uptake. The swelling of the parasitized erythrocyte results in an increase in its osmotic fragility. Countering cell swelling by increasing the osmolarity of the extracellular medium reduces the antiplasmodial efficacy of PfATP4-associated compounds, consistent with cell swelling playing a role in the antimalarial activity of this class of compounds.
Publisher: American Chemical Society (ACS)
Date: 24-03-2014
DOI: 10.1021/ML5000228
Publisher: Wiley
Date: 15-09-2014
DOI: 10.1111/MMI.12765
Abstract: The antimalarial spiroindolones disrupt Plasmodium falciparum Na(+) regulation and induce an alkalinization of the parasite cytosol. It has been proposed that they do so by inhibiting PfATP4, a parasite plasma membrane P-type ATPase postulated to export Na(+) and import H(+) equivalents. Here, we screened the 400 antiplasmodial compounds of the open access 'Malaria Box' for their effects on parasite ion regulation. Twenty eight compounds affected parasite Na(+) and pH regulation in a manner consistent with PfATP4 inhibition. Six of these, with chemically erse structures, were selected for further analysis. All six showed reduced antiplasmodial activity against spiroindolone-resistant parasites carrying mutations in pfatp4. We exposed parasites to incrementally increasing concentrations of two of the six compounds and in both cases obtained resistant parasites with mutations in pfatp4. The finding that erse chemotypes have an apparently similar mechanism of action indicates that PfATP4 may be a significant Achilles' heel for the parasite.
Publisher: Wiley
Date: 08-2010
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.EJMECH.2022.114324
Abstract: Malaria remains a prevalent infectious disease in developing countries. The first-line therapeutic options are based on combinations of fast-acting artemisinin derivatives and longer-acting synthetic drugs. However, the emergence of resistance to these first-line treatments represents a serious risk, and the discovery of new effective drugs is urgently required. For this reason, new antimalarial chemotypes with new mechanisms of action, and ideally with activity against multiple parasite stages, are needed. We report a new scaffold with dual-stage (blood and liver) antiplasmodial activity. Twenty-six spirooxadiazoline oxindoles were synthesized and screened against the erythrocytic stage of the human malaria parasite P. falciparum. The most active compounds were also tested against the liver-stage of the murine parasite P. berghei. Seven compounds emerged as dual-stage antimalarials, with IC
Publisher: Portland Press Ltd.
Date: 21-11-2014
DOI: 10.1042/BSR20140134
Abstract: Although efforts to understand the basis for inter-strain phenotypic variation in the most virulent malaria species, Plasmodium falciparum, have benefited from advances in genomic technologies, there have to date been few metabolomic studies of this parasite. Using 1H-NMR spectroscopy, we have compared the metabolite profiles of red blood cells infected with different P. falciparum strains. These included both chloroquine-sensitive and chloroquine-resistant strains, as well as transfectant lines engineered to express different isoforms of the chloroquine-resistance-conferring pfcrt (P. falciparum chloroquine resistance transporter). Our analyses revealed strain-specific differences in a range of metabolites. There was marked variation in the levels of the membrane precursors choline and phosphocholine, with some strains having & -fold higher choline levels and & -fold higher phosphocholine levels than others. Chloroquine-resistant strains showed elevated levels of a number of amino acids relative to chloroquine-sensitive strains, including an approximately 2-fold increase in aspartate levels. The elevation in amino acid levels was attributable to mutations in pfcrt. Pfcrt-linked differences in amino acid abundance were confirmed using alternate extraction and detection (HPLC) methods. Mutations acquired to withstand chloroquine exposure therefore give rise to significant biochemical alterations in the parasite.
Publisher: Portland Press Ltd.
Date: 21-06-2005
DOI: 10.1042/BJ20050102
Abstract: The Shigella flexneri serotypes differ in the nature of their O-antigens. The addition of glucosyl or O-acetyl groups to the common backbone repeat units gives rise to the different serotypes. GtrII glucosylates rhamnose III of the O-antigen repeat unit, thus converting serotype Y (which has no modifications to the basic O-antigen repeat unit) into serotype 2a, the most prevalent serotype. In the present study, the topology of GtrII has been determined. GtrII has nine transmembrane helices, a re-entrant loop and three large periplasmic regions. Four critical residues (Glu40, Phe414, Cys435 and Lys478) were identified in two of the periplasmic regions. Despite the lack of sequence similarity between GtrII and the Gtrs from other serotypes, three of the critical residues identified are conserved in the remaining Gtrs. This is consistent with some degree of mechanistic conservation in this functionally related group of proteins.
Publisher: American Chemical Society (ACS)
Date: 16-11-2016
Publisher: Springer Science and Business Media LLC
Date: 19-10-2021
DOI: 10.1186/S13007-021-00806-6
Abstract: The need for rapid in-field measurement of key traits contributing to yield over many thousands of genotypes is a major roadblock in crop breeding. Recently, leaf hyperspectral reflectance data has been used to train machine learning models using partial least squares regression (PLSR) to rapidly predict genetic variation in photosynthetic and leaf traits across wheat populations, among other species. However, the application of published PLSR spectral models is limited by a fixed spectral wavelength range as input and the requirement of separate custom-built models for each trait and wavelength range. In addition, the use of reflectance spectra from the short-wave infrared region requires expensive multiple detector spectrometers. The ability to train a model that can accommodate input from different spectral ranges would potentially make such models extensible to more affordable sensors. Here we compare the accuracy of prediction of PLSR with various deep learning approaches and an ensemble model, each trained and tested using previously published data sets. We demonstrate that the accuracy of PLSR to predict photosynthetic and related leaf traits in wheat can be improved with deep learning-based and ensemble models without overfitting. Additionally, these models can be flexibly applied across spectral ranges without significantly compromising accuracy. The method reported provides an improved prediction of wheat leaf and photosynthetic traits from leaf hyperspectral reflectance and do not require a full range, high cost leaf spectrometer. We provide a web service for deploying these algorithms to predict physiological traits in wheat from a variety of spectral data sets, with important implications for wheat yield prediction and crop breeding.
Publisher: American Society for Microbiology
Date: 05-2011
DOI: 10.1128/AAC.01167-10
Abstract: Mutant forms of the Plasmodium falciparum chloroquine resistance transporter (PfCRT) mediate chloroquine resistance by effluxing the drug from the parasite's digestive vacuole, the acidic organelle in which chloroquine exerts its parasiticidal effect. However, different parasites bearing the same mutant form of PfCRT can vary substantially in their chloroquine susceptibility. Here, we have investigated the biochemical basis for the difference in chloroquine response among transfectant parasite lines having different genetic backgrounds but bearing the same mutant form of PfCRT. Despite showing significant differences in their chloroquine susceptibility, all lines with the mutant PfCRT showed a similar chloroquine-induced H + leak from the digestive vacuole, indicative of similar rates of PfCRT-mediated chloroquine efflux. Furthermore, all lines showed similarly reduced levels of drug accumulation. Factors other than chloroquine efflux and accumulation therefore influence the susceptibility to this drug in parasites expressing mutant PfCRT. Furthermore, in some but not all strains bearing mutant PfCRT, the 50% inhibitory concentration (IC 50 ) for chloroquine and the degree of resistance compared to that of recombinant control parasites varied with the length of the parasite growth assays. In these parasites, the 50% inhibitory concentration for chloroquine measured in 72- or 96-h assays was significantly lower than that measured in 48-h assays. This highlights the importance of considering the first- and second-cycle activities of chloroquine in future studies of parasite susceptibility to this drug.
Publisher: The Company of Biologists
Date: 15-05-2008
DOI: 10.1242/JCS.016758
Abstract: Chloroquine resistance in the malaria parasite Plasmodium falciparum has made malaria increasingly difficult to control. Chloroquine-resistant parasites accumulate less chloroquine than their chloroquine-sensitive counterparts however, the mechanism underlying this remains unclear. The primary site of accumulation and antimalarial action of chloroquine is the internal acidic digestive vacuole of the parasite, the acidity of which is maintained by inwardly-directed H+ pumps, working against the (outward) leak of H+. In this study we have investigated the leak of H+ from the digestive vacuole of the parasite by monitoring the alkalinisation of the vacuole following inhibition of the H+-pumping V-type ATPase by concanamycin A. The rates of alkalinisation observed in three chloroquine-resistant strains were two- to fourfold higher than those measured in three chloroquine-sensitive strains. On addition of chloroquine there was a dramatic increase in the rate of alkalinisation in the chloroquine-resistant strains, whereas chloroquine caused the rate of alkalinisation to decrease in the chloroquine-sensitive strains. The chloroquine-associated increase in the rate of alkalinisation seen in chloroquine-resistant parasites was inhibited by the chloroquine-resistance reversal agent verapamil. The data are consistent with the hypothesis that in chloroquine-resistant parasites chloroquine effluxes from the digestive vacuole, in association with H+, via a verapamil-sensitive pathway.
Publisher: American Chemical Society (ACS)
Date: 06-11-2020
DOI: 10.26434/CHEMRXIV.13194755
Abstract: The discovery of new antimalarial medicines with novel mechanisms of action is key to combating the problem of increasing resistance to our frontline treatments. The Open Source Malaria (OSM) consortium has been developing compounds ("Series 4") that have potent activity against i Plasmodium falciparum /i i in vitro /i and i in vivo /i and that have been suggested to act through the inhibition of i Pf /i ATP4, an essential membrane ion pump that regulates the parasite’s intracellular Na sup + /sup concentration. The structure of i Pf /i ATP4 is yet to be determined. In the absence of structural information about this target, a public competition was created to develop a model that would allow the prediction of anti- i Pf /i ATP4 activity among Series 4 compounds, thereby reducing project costs associated with the unnecessary synthesis of inactive compounds. In the first round, in 2016, six participants used the open data collated by OSM to develop moderately predictive models using erse methods. Notably, all submitted models were available to all other participants in real time. Since then further bioactivity data have been acquired and machine learning methods have rapidly developed, so a second round of the competition was undertaken, in 2019, again with freely-donated models that other participants could see. The best-performing models from this second round were used to predict novel inhibitory molecules, of which several were synthesised and evaluated against the parasite. One such compound, containing a motif that the human chemists familiar with this series would have dismissed as ill-advised, was active. The project demonstrated the abilities of new machine learning methods in the prediction of active compounds where there is no biological target structure, frequently the central problem in phenotypic drug discovery. Since all data and participant interactions remain in the public domain, this research project “lives” and may be improved by others.
Publisher: American Chemical Society (ACS)
Date: 22-02-2023
Publisher: Elsevier BV
Date: 08-2018
Publisher: American Society for Microbiology
Date: 12-2008
DOI: 10.1128/AAC.00666-08
Abstract: Chloroquine resistance in the malaria parasite Plasmodium falciparum is conferred by mutations in the P. falciparum c hloroquine r esistance t ransporter (PfCRT). PfCRT localizes to the membrane of the parasite's internal digestive vacuole, an acidic organelle in which chloroquine accumulates to high concentrations and exerts its toxic effect. Mutations in PfCRT are thought to reduce chloroquine accumulation in this organelle. How they do so is the subject of ongoing debate. Recently we have shown that in the presence of chloroquine there is an increased leak of H + from the digestive vacuole in chloroquine-resistant but not chloroquine-sensitive parasites. Here, using transfectant parasite strains of a single genetic background and differing only in their pfcrt allele, we show that chloroquine resistance-conferring PfCRT mutations are responsible for this chloroquine-associated H + leak. This is consistent with the hypothesis that the chloroquine resistance-conferring forms of PfCRT mediate the efflux of chloroquine, in association with H + , from the malaria parasite's digestive vacuole.
Publisher: Archives of Pathology and Laboratory Medicine
Date: 30-11-2018
DOI: 10.5858/ARPA.2018-0411-SA
Abstract: The International Collaboration on Cancer Reporting is a nonprofit organization whose goal is to develop evidence-based, internationally agreed-upon standardized data sets for each cancer site for use throughout the world. Providing global standardization of pathology tumor classification, staging, and other reporting elements will lead to the objective of improved patient management and enhanced epidemiologic research. Carcinomas of the oral cavity continue to represent a significant oncologic management burden, especially as changes in alcohol and tobacco use on a global scale contribute to tumor development. Separation of oral cavity carcinomas from oropharyngeal tumors is also important, as management and outcome are quite different when human papillomavirus association is taken into consideration. Topics such as tumor thickness versus depth of invasion, pattern of invasive front, extent and size of perineural invasion, and margin assessment all contribute to accurate classification and staging of tumors. This review focuses on the data set developed for Carcinomas of the Oral Cavity Histopathology Reporting Guide, with discussion of the key elements developed for inclusion.
Publisher: American Chemical Society (ACS)
Date: 08-11-2021
DOI: 10.1021/ACS.JMEDCHEM.1C00313
Abstract: The Open Source Malaria (OSM) consortium is developing compounds that kill the human malaria parasite,
Publisher: American Chemical Society (ACS)
Date: 06-01-2014
DOI: 10.1021/CB4008953
Publisher: Wiley
Date: 20-10-2008
DOI: 10.1111/J.1365-2958.2008.06451.X
Abstract: The human malaria parasite, Plasmodium falciparum, has long been known to have a homologue of the human 'multidrug resistance' P-glycoprotein. P-glycoprotein is an ABC transporter that pumps drugs from multidrug-resistant cancer cells. The malaria parasite's P-glycoprotein homologue, Pgh1, is known to influence the sensitivity of malaria parasites to a erse range of antimalarial drugs, but the mechanism by which it does so has remained obscure. In a new paper, Sanchez et al. report the successful functional expression of Pgh1 in Xenopus laevis oocytes and provide the first direct demonstration of the ability of Pgh1 to transport drugs. The work provides important new insights into the mechanism by which Pgh1 influences malaria parasite drug sensitivity.
Publisher: Springer London
Date: 2012
Publisher: Springer Science and Business Media LLC
Date: 16-07-2019
DOI: 10.1038/S41598-019-46500-5
Abstract: We developed a novel series of antimalarial compounds based on a 4-cyano-3-methylisoquinoline. Our lead compound MB14 achieved modest inhibition of the growth in vitro of the human malaria parasite, Plasmodium falciparum . To identify its biological target we selected for parasites resistant to MB14. Genome sequencing revealed that all resistant parasites bore a single point S374R mutation in the sodium (Na + ) efflux transporter PfATP4. There are many compounds known to inhibit PfATP4 and some are under preclinical development. MB14 was shown to inhibit Na + dependent ATPase activity in parasite membranes, consistent with the compound targeting PfATP4 directly. PfATP4 inhibitors cause swelling and lysis of infected erythrocytes, attributed to the accumulation of Na + inside the intracellular parasites and the resultant parasite swelling. We show here that inhibitor-induced lysis of infected erythrocytes is dependent upon the parasite protein RhopH2, a component of the new permeability pathways that are induced by the parasite in the erythrocyte membrane. These pathways mediate the influx of Na + into the infected erythrocyte and their suppression via RhopH2 knockdown limits the accumulation of Na + within the parasite hence protecting the infected erythrocyte from lysis. This study reveals a role for the parasite-induced new permeability pathways in the mechanism of action of PfATP4 inhibitors.
Publisher: Springer Science and Business Media LLC
Date: 30-09-2022
DOI: 10.1038/S41467-022-33403-9
Abstract: Diverse compounds target the Plasmodium falciparum Na + pump PfATP4, with cipargamin and (+)-SJ733 the most clinically-advanced. In a recent clinical trial for cipargamin, recrudescent parasites emerged, with most having a G358S mutation in PfATP4. Here, we show that PfATP4 G358S parasites can withstand micromolar concentrations of cipargamin and (+)-SJ733, while remaining susceptible to antimalarials that do not target PfATP4. The G358S mutation in PfATP4, and the equivalent mutation in Toxoplasma gondii ATP4, decrease the sensitivity of ATP4 to inhibition by cipargamin and (+)-SJ733, thereby protecting parasites from disruption of Na + regulation. The G358S mutation reduces the affinity of PfATP4 for Na + and is associated with an increase in the parasite’s resting cytosolic [Na + ]. However, no defect in parasite growth or transmissibility is observed. Our findings suggest that PfATP4 inhibitors in clinical development should be tested against PfATP4 G358S parasites, and that their combination with unrelated antimalarials may mitigate against resistance development.
Publisher: Elsevier BV
Date: 2007
Location: Sri Lanka
No related grants have been discovered for Adele Lehane.