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1. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase

Author

Xie, Stanley C., Wang, Yinuo, Morton, Craig J., Metcalfe, Riley D., Dogovski, Con, Pasaje, Charisse Flerida A., Dunn, Elyse, Luth, Madeline R., Kumpornsin, Krittikorn, Istvan, Eva S., Park, Joon Sung, Fairhurst, Kate J., Ketprasit, Nutpakal, Yeo, Tomas, Yildirim, Okan, Bhebhe, Mathamsanqa N., Klug, Dana M., Rutledge, Peter J., Godoy, Luiz C., Dey, Sumanta, De Souza, Mariana Laureano, Siqueira-Neto, Jair L., Du, Yawei, Puhalovich, Tanya, Amini, Mona, Shami, Gerry, Loesbanluechai, Duangkamon, Nie, Shuai, Williamson, Nicholas, Jana, Gouranga P., Maity, Bikash C., Thomson, Patrick, Foley, Thomas, Tan, Derek S., Niles, Jacquin C., Han, Byung Woo, Goldberg, Daniel E., Burrows, Jeremy, Fidock, David A., Lee, Marcus C. S., Winzeler, Elizabeth A., Griffin, Michael D. W., Todd, Matthew H., and Tilley, Leann

Published
2024
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2. Design of proteasome inhibitors with oral efficacy in vivo against Plasmodium falciparum and selectivity over the human proteasome

Author

Xie, Stanley C., Metcalfe, Riley D., Mizutani, Hirotake, Puhalovich, Tanya, Hanssen, Eric, Morton, Craig J., Du, Yawei, Dogovski, Con, Huang, Shih-Chung, Ciavarri, Jeffrey, Hales, Paul, Griffin, Robert J., Cohen, Lawrence H., Chuang, Bei-Ching, Wittlin, Sergio, Deni, Ioanna, Yeo, Tomas, Ward, Kurt E., Barry, Daniel C., Liu, Boyin, Gillett, David L., Crespo-Fernandez, Benigno F., Ottilie, Sabine, Mittal, Nimisha, Churchyard, Alisje, Ferguson, Daniel, Aguiar, Anna Caroline C., Guido, Rafael V. C., Baum, Jake, Hanson, Kirsten K., Winzeler, Elizabeth A., Gamo, Francisco-Javier, Fidock, David A., Baud, Delphine, Parker, Michael W., Brand, Stephen, Dick, Lawrence R., Griffin, Michael D. W., Gould, Alexandra E., and Tilley, Leann

Published
2021

3. A dynamic stress model explains the delayed drug effect in artemisinin treatment of Plasmodium falciparum

Author

Cao, Pengxing, Klonis, Nectarios, Zaloumis, Sophie, Dogovski, Con, Xie, Stanley C., Saralamba, Sompob, White, Lisa J., Fowkes, Freya J. I., Tilley, Leann, Simpson, Julie A., and McCaw, James M.

Subjects
Quantitative Biology - Populations and Evolution, 92B05
Abstract

Artemisinin resistance constitutes a major threat to the continued success of control programs for malaria. With alternative antimalarial drugs not yet available, improving our understanding of how artemisinin-based drugs act and how resistance manifests is essential to enable optimisation of dosing regimens in order to prolong the lifespan of current first-line treatment options. Here, through introduction of a novel model of the dynamics of the parasites' response to drug, we explore how artemisinin-based therapies may be adjusted to maintain efficacy and how artemisinin resistance may manifest and be overcome. We introduce a dynamic mathematical model, extending on the traditional pharmacokinetic-pharmacodynamic framework, to capture the time-dependent development of a stress response in parasites. We fit the model to in vitro data and establish that the parasites' stress response explains the recently identified complex interplay between drug concentration, exposure time and parasite viability. Our model demonstrates that the previously reported hypersensitivity of early ring stage parasites of the 3D7 strain to dihydroartemisinin (DHA) is primarily due to the rapid development of stress, rather than any change in the maximum achievable killing rate. Of direct clinical relevance, we demonstrate that the complex temporal features of artemisinin action observed in vitro have a significant impact on predictions of in vivo parasite clearance using PK-PD models. Given the important role that such models play in the design and evaluation of clinical trials for alternative drug dosing regimens, our model contributes an enhanced predictive platform for the continued efforts to minimise the burden of malaria., Comment: 24 Pages, 9 figures, 2 tables

Published
2016
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5. Structure- and function-based design of Plasmodium-selective proteasome inhibitors

Author

Li, Hao, O’Donoghue, Anthony J, van der Linden, Wouter A, Xie, Stanley C, Yoo, Euna, Foe, Ian T, Tilley, Leann, Craik, Charles S, da Fonseca, Paula CA, and Bogyo, Matthew

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Good Health and Well Being, Animals, Antimalarials, Artemisinins, Catalytic Domain, Cryoelectron Microscopy, Dose-Response Relationship, Drug, Drug Design, Drug Resistance, Drug Synergism, Enzyme Activation, Female, Humans, Mice, Mice, Inbred BALB C, Models, Molecular, Plasmodium, Plasmodium chabaudi, Plasmodium falciparum, Proteasome Endopeptidase Complex, Proteasome Inhibitors, Protein Subunits, Species Specificity, Substrate Specificity, General Science & Technology
Abstract

The proteasome is a multi-component protease complex responsible for regulating key processes such as the cell cycle and antigen presentation. Compounds that target the proteasome are potentially valuable tools for the treatment of pathogens that depend on proteasome function for survival and replication. In particular, proteasome inhibitors have been shown to be toxic for the malaria parasite Plasmodium falciparum at all stages of its life cycle. Most compounds that have been tested against the parasite also inhibit the mammalian proteasome, resulting in toxicity that precludes their use as therapeutic agents. Therefore, better definition of the substrate specificity and structural properties of the Plasmodium proteasome could enable the development of compounds with sufficient selectivity to allow their use as anti-malarial agents. To accomplish this goal, here we use a substrate profiling method to uncover differences in the specificities of the human and P. falciparum proteasome. We design inhibitors based on amino-acid preferences specific to the parasite proteasome, and find that they preferentially inhibit the β2-subunit. We determine the structure of the P. falciparum 20S proteasome bound to the inhibitor using cryo-electron microscopy and single-particle analysis, to a resolution of 3.6 Å. These data reveal the unusually open P. falciparum β2 active site and provide valuable information about active-site architecture that can be used to further refine inhibitor design. Furthermore, consistent with the recent finding that the proteasome is important for stress pathways associated with resistance of artemisinin family anti-malarials, we observe growth inhibition synergism with low doses of this β2-selective inhibitor in artemisinin-sensitive and -resistant parasites. Finally, we demonstrate that a parasite-selective inhibitor could be used to attenuate parasite growth in vivo without appreciable toxicity to the host. Thus, the Plasmodium proteasome is a chemically tractable target that could be exploited by next-generation anti-malarial agents.

Published
2016

7. Hijacking tRNA charging process: a novel approach to combat malaria

Author

Ketprasit, Nutpakal, primary, Xie, Stanley C., additional, Dogovski, Con, additional, Park, Joon Sung, additional, Morton, Craig J., additional, Hilko, David, additional, Dunn, Elyse, additional, Amini, Mona, additional, Nie, Shuai, additional, Williamson, Nicholas, additional, Poulsen, Sally-Ann, additional, Han, Byung Woo, additional, Griffin, Michael D. W., additional, and Tilley, Leann, additional

Published
2023
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8. Targeting Aminoacyl tRNA Synthetases for Antimalarial Drug Development.

Author

Xie, Stanley C., Griffin, Michael D.W., Winzeler, Elizabeth A., Ribas de Pouplana, Lluis, and Tilley, Leann

Abstract

Infections caused by malaria parasites place an enormous burden on the world's poorest communities. Breakthrough drugs with novel mechanisms of action are urgently needed. As an organism that undergoes rapid growth and division, the malaria parasite Plasmodium falciparum is highly reliant on protein synthesis, which in turn requires aminoacyl-tRNA synthetases (aaRSs) to charge tRNAs with their corresponding amino acid. Protein translation is required at all stages of the parasite life cycle; thus, aaRS inhibitors have the potential for whole-of-life-cycle antimalarial activity. This review focuses on efforts to identify potent plasmodium-specific aaRS inhibitors using phenotypic screening, target validation, and structure-guided drug design. Recent work reveals that aaRSs are susceptible targets for a class of AMP-mimicking nucleoside sulfamates that target the enzymes via a novel reaction hijacking mechanism. This finding opens up the possibility of generating bespoke inhibitors of different aaRSs, providing new drug leads. [ABSTRACT FROM AUTHOR]

Published
2023
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10. Reaction hijacking of tyrosine tRNA synthetase as a new whole-of-life-cycle antimalarial strategy

Author

Xie, Stanley C., primary, Metcalfe, Riley D., additional, Dunn, Elyse, additional, Morton, Craig J., additional, Huang, Shih-Chung, additional, Puhalovich, Tanya, additional, Du, Yawei, additional, Wittlin, Sergio, additional, Nie, Shuai, additional, Luth, Madeline R., additional, Ma, Liting, additional, Kim, Mi-Sook, additional, Pasaje, Charisse Flerida A., additional, Kumpornsin, Krittikorn, additional, Giannangelo, Carlo, additional, Houghton, Fiona J., additional, Churchyard, Alisje, additional, Famodimu, Mufuliat T., additional, Barry, Daniel C., additional, Gillett, David L., additional, Dey, Sumanta, additional, Kosasih, Clara C., additional, Newman, William, additional, Niles, Jacquin C., additional, Lee, Marcus C. S., additional, Baum, Jake, additional, Ottilie, Sabine, additional, Winzeler, Elizabeth A., additional, Creek, Darren J., additional, Williamson, Nicholas, additional, Parker, Michael W., additional, Brand, Stephen, additional, Langston, Steven P., additional, Dick, Lawrence R., additional, Griffin, Michael D.W., additional, Gould, Alexandra E., additional, and Tilley, Leann, additional

Published
2022
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12. High Throughput Screening to Identify Selective and Nonpeptidomimetic Proteasome Inhibitors As Antimalarials

Author

Mata-Cantero, Lydia, primary, Xie, Stanley C., additional, García, Mercedes, additional, Coyle, Joanne, additional, Fernandez, Raquel, additional, Cabrera, Alvaro Cortes, additional, Gillett, David L., additional, Crespo, Benigno, additional, Gamo, Francisco-Javier, additional, Fernández, Esther, additional, Tilley, Leann, additional, and Gomez-Lorenzo, Maria G., additional

Published
2021
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14. Decreased K13 Abundance Reduces Hemoglobin Catabolism and Proteotoxic Stress, Underpinning Artemisinin Resistance

Author

Yang, Tuo, primary, Yeoh, Lee M., additional, Tutor, Madel V., additional, Dixon, Matthew W., additional, McMillan, Paul J., additional, Xie, Stanley C., additional, Bridgford, Jessica L., additional, Gillett, David L., additional, Duffy, Michael F., additional, Ralph, Stuart A., additional, McConville, Malcolm J., additional, Tilley, Leann, additional, and Cobbold, Simon A., additional

Published
2019
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16. The structure of the Plasmodium falciparum 20S proteasome in complex with the PA28 activator

Author

Metcalfe, Riley D., primary, Xie, Stanley C., additional, Hanssen, Eric, additional, Yang, Tuo, additional, Gillett, David L., additional, Leis, Andrew, additional, Morton, Craig J., additional, Kuiper, Michael J., additional, Parker, Michael W., additional, Spillman, Natalie J., additional, Wong, Wilson, additional, Tsu, Christopher, additional, Dick, Lawrence R., additional, Griffin, Michael D. W., additional, and Tilley, Leann, additional

Published
2019
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17. Target Validation and Identification of Novel Boronate Inhibitors of the Plasmodium falciparum Proteasome

Author

Xie, Stanley C., primary, Gillett, David L., additional, Spillman, Natalie J., additional, Tsu, Christopher, additional, Luth, Madeline R., additional, Ottilie, Sabine, additional, Duffy, Sandra, additional, Gould, Alexandra E., additional, Hales, Paul, additional, Seager, Benjamin A., additional, Charron, Carlie L., additional, Bruzzese, Frank, additional, Yang, Xiaofeng, additional, Zhao, Xiansi, additional, Huang, Shih-Chung, additional, Hutton, Craig A., additional, Burrows, Jeremy N., additional, Winzeler, Elizabeth A., additional, Avery, Vicky M., additional, Dick, Lawrence R., additional, and Tilley, Leann, additional

Published
2018
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20. Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Author

Dogovski, Con, Xie, Stanley C., Burgio, Gaetan, Bridgford, Jess, Mok, Sachel, McCaw, James M., Chotivanich, Kesinee, Kenny, Shannon, Gnädig, Nina, Straimer, Judith, Bozdech, Zbynek, Fidock, David A., Simpson, Julie A., Dondorp, Arjen M., Foote, Simon, Klonis, Nectarios, Tilley, Leann, Dogovski, Con, Xie, Stanley C., Burgio, Gaetan, Bridgford, Jess, Mok, Sachel, McCaw, James M., Chotivanich, Kesinee, Kenny, Shannon, Gnädig, Nina, Straimer, Judith, Bozdech, Zbynek, Fidock, David A., Simpson, Julie A., Dondorp, Arjen M., Foote, Simon, Klonis, Nectarios, and Tilley, Leann

Abstract

Successful control of falciparum malaria depends greatly on treatment with artemisinin combination therapies. Thus, reports that resistance to artemisinins (ARTs) has emerged, and that the prevalence of this resistance is increasing, are alarming. ART resistance has recently been linked to mutations in the K13 propeller protein. We undertook a detailed kinetic analysis of the drug responses of K13 wild-type and mutant isolates of Plasmodium falciparum sourced from a region in Cambodia (Pailin). We demonstrate that ART treatment induces growth retardation and an accumulation of ubiquitinated proteins, indicative of a cellular stress response that engages the ubiquitin/proteasome system. We show that resistant parasites exhibit lower levels of ubiquitinated proteins and delayed onset of cell death, indicating an enhanced cell stress response. We found that the stress response can be targeted by inhibiting the proteasome. Accordingly, clinically used proteasome inhibitors strongly synergize ART activity against both sensitive and resistant parasites, including isogenic lines expressing mutant or wild-type K13. Synergy is also observed against Plasmodium berghei in vivo. We developed a detailed model of parasite responses that enables us to infer, for the first time, in vivo parasite clearance profiles from in vitro assessments of ART sensitivity. We provide evidence that the clinical marker of resistance (delayed parasite clearance) is an indirect measure of drug efficacy because of the persistence of unviable parasites with unchanged morphology in the circulation, and we suggest alternative approaches for the direct measurement of viability. Our model predicts that extending current three-day ART treatment courses to four days, or splitting the doses, will efficiently clear resistant parasite infections. This work provides a rationale for improving the detection of ART resistance in the field and for treatment strategies that can be employed in areas with ART resistan

Published
2015

21. Targeting the Cell Stress Response of Plasmodium falciparum to Overcome Artemisinin Resistance

Author

Dogovski, Con, primary, Xie, Stanley C., additional, Burgio, Gaetan, additional, Bridgford, Jess, additional, Mok, Sachel, additional, McCaw, James M., additional, Chotivanich, Kesinee, additional, Kenny, Shannon, additional, Gnädig, Nina, additional, Straimer, Judith, additional, Bozdech, Zbynek, additional, Fidock, David A., additional, Simpson, Julie A., additional, Dondorp, Arjen M., additional, Foote, Simon, additional, Klonis, Nectarios, additional, and Tilley, Leann, additional

Published
2015
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24. Haemoglobin degradation underpins the sensitivity of early ring stage Plasmodium falciparum to artemisinins.

Author

Xie, Stanley C., Dogovski, Con, Hanssen, Eric, Chiu, Francis, Tuo Yang, Crespo, Maria P., Stafford, Che, Batinovic, Steven, Teguh, Silvia, Charman, Susan, Klonis, Nectarios, and Tilley, Leann

Subjects
*HEMOGLOBINS, *PLASMODIUM falciparum, *ARTEMISININ, *NUTRITION, *ANTIPROTOZOAL agents
Abstract

Current first-line artemisinin antimalarials are threatened by the emergence of resistant Plasmodium falciparum. Decreased sensitivity is evident in the initial (early ring) stage of intraerythrocytic development, meaning that it is crucial to understand the action of artemisinins at this stage. Here, we examined the roles of iron (Fe) ions and haem in artemisinin activation in early rings using Fe ion chelators and a specific haemoglobinase inhibitor (E64d). Quantitative modelling of the antagonism accounted for its complex dependence on the chemical features of the artemisinins and on the drug exposure time, and showed that almost all artemisinin activity in early rings (>80%) is due to haem-mediated activation. The surprising implication that haemoglobin uptake and digestion is active in early rings is supported by identification of active haemoglobinases (falcipains) at this stage. Genetic down-modulation of the expression of the two main cysteine protease haemoglobinases, falcipains2and3,renders early ring stage parasites resistant to artemisinins. This confirms the important role of haemoglobin-degrading falcipains in artemisinin activation, and shows that changes in the rate of artemisinin activation could mediate high-level artemisinin resistance. [ABSTRACT FROM AUTHOR]

Published
2016
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25. Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Author

Xie SC, Wang Y, Morton CJ, Metcalfe RD, Dogovski C, Pasaje CFA, Dunn E, Luth MR, Kumpornsin K, Istvan ES, Park JS, Fairhurst KJ, Ketprasit N, Yeo T, Yildirim O, Bhebhe MN, Klug DM, Rutledge PJ, Godoy LC, Dey S, De Souza ML, Siqueira-Neto JL, Du Y, Puhalovich T, Amini M, Shami G, Loesbanluechai D, Nie S, Williamson N, Jana GP, Maity BC, Thomson P, Foley T, Tan DS, Niles JC, Han BW, Goldberg DE, Burrows J, Fidock DA, Lee MCS, Winzeler EA, Griffin MDW, Todd MH, and Tilley L

Abstract

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl tRNA synthetase ( Pf AsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of Pf AsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound Pf AsnRS provide insights into the structure activity relationship and the selectivity mechanism., Competing Interests: Competing interests. The authors have no competing interests to declare.

Published
2023
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