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1. Author Correction: Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Author

Wyllie, Susan, Thomas, Michael, Patterson, Stephen, Crouch, Sabrinia, De Rycker, Manu, Lowe, Rhiannon, Gresham, Stephanie, Urbaniak, Michael D., Otto, Thomas D., Stojanovski, Laste, Simeons, Frederick R. C., Manthri, Sujatha, MacLean, Lorna M., Zuccotto, Fabio, Homeyer, Nadine, Pflaumer, Hannah, Boesche, Markus, Sastry, Lalitha, Connolly, Paul, Albrecht, Sebastian, Berriman, Matt, Drewes, Gerard, Gray, David W., Ghidelli-Disse, Sonja, Dixon, Susan, Fiandor, Jose M., Wyatt, Paul G., Ferguson, Michael A. J., Fairlamb, Alan H., Miles, Timothy J., Read, Kevin D., and Gilbert, Ian H.

Published
2023
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3. Sterol 14-alpha demethylase (CYP51) activity in Leishmania donovani is likely dependent upon cytochrome P450 reductase 1.

Author

Tulloch, Lindsay B., Tinti, Michele, Wall, Richard J., Weidt, Stefan K., Corpas- Lopez, Victoriano, Dey, Gourav, Smith, Terry K., Fairlamb, Alan H., Barrett, Michael P., and Wyllie, Susan

Subjects
CYTOCHROME P-450, LEISHMANIA donovani, DEMETHYLASE, VISCERAL leishmaniasis, AMPHOTERICIN B, PHYTOSTEROLS
Abstract

Liposomal amphotericin B is an important frontline drug for the treatment of visceral leishmaniasis, a neglected disease of poverty. The mechanism of action of amphotericin B (AmB) is thought to involve interaction with ergosterol and other ergostane sterols, resulting in disruption of the integrity and key functions of the plasma membrane. Emergence of clinically refractory isolates of L. donovani and L. infantum is an ongoing issue and knowledge of potential resistance mechanisms can help to alleviate this problem. Here we report the characterisation of four independently selected L. donovani clones that are resistant to AmB. Whole genome sequencing revealed that in three of the moderately resistant clones, resistance was due solely to the deletion of a gene encoding C24-sterol methyltransferase (SMT1). The fourth, hyper-resistant resistant clone (>60-fold) was found to have a 24 bp deletion in both alleles of a gene encoding a putative cytochrome P450 reductase (P450R1). Metabolic profiling indicated these parasites were virtually devoid of ergosterol (0.2% versus 18% of total sterols in wild-type) and had a marked accumulation of 14-methylfecosterol (75% versus 0.1% of total sterols in wild-type) and other 14-alpha methylcholestanes. These are substrates for sterol 14-alpha demethylase (CYP51) suggesting that this enzyme may be a bona fide P450R specifically involved in electron transfer from NADPH to CYP51 during catalysis. Deletion of P450R1 in wild-type cells phenocopied the metabolic changes observed in our AmB hyper-resistant clone as well as in CYP51 nulls. Likewise, addition of a wild type P450R1 gene restored sterol profiles to wild type. Our studies indicate that P450R1 is essential for L. donovani amastigote viability, thus loss of this gene is unlikely to be a driver of clinical resistance. Nevertheless, investigating the mechanisms underpinning AmB resistance in these cells provided insights that refine our understanding of the L. donovani sterol biosynthetic pathway. Author summary: The antifungal drug, amphotericin B, is also used in the treatment of visceral leishmaniasis, a potentially lethal parasitic disease infecting the specialised immune cells (macrophages) in the liver, spleen, and bone marrow. Treatment failures due to emerging drug resistance are a significant concern. Using a combination of genetic and biochemical approaches, we have confirmed the mechanisms by which these parasites become less sensitive to treatment with amphotericin B. In addition, we have identified a novel mechanism involving loss of a key enzyme (cytochrome P450 reductase 1) in the biosynthetic pathway to ergosterol, an important lipid component of the parasite's plasma membrane. These studies increase our fundamental understanding of this important metabolic pathway and provide information that may be exploited to develop novel therapeutic strategies to combat this killer disease. [ABSTRACT FROM AUTHOR]

Published
2024
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4. Antikinetoplastid SAR study in 3-nitroimidazopyridine series: Identification of a novel non-genotoxic and potent anti-T. b. brucei hit-compound with improved pharmacokinetic properties

Author

Fersing, Cyril, Boudot, Clotilde, Paoli-Lombardo, Romain, Primas, Nicolas, Pinault, Emilie, Hutter, Sébastien, Castera-Ducros, Caroline, Kabri, Youssef, Pedron, Julien, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Stigliani, Jean-Luc, Valentin, Alexis, Azqueta, Amaya, Muruzabal, Damián, Destere, Alexandre, Wyllie, Susan, Fairlamb, Alan H., Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Di Giorgio, Carole, Rathelot, Pascal, Azas, Nadine, Courtioux, Bertrand, Vanelle, Patrice, and Verhaeghe, Pierre

Published
2020
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5. 8-Alkynyl-3-nitroimidazopyridines display potent antitrypanosomal activity against both T. b. brucei and cruzi

Author

Fersing, Cyril, Boudot, Clotilde, Castera-Ducros, Caroline, Pinault, Emilie, Hutter, Sébastien, Paoli-Lombardo, Romain, Primas, Nicolas, Pedron, Julien, Seguy, Line, Bourgeade-Delmas, Sandra, Sournia-Saquet, Alix, Stigliani, Jean-Luc, Brossas, Jean-Yves, Paris, Luc, Valentin, Alexis, Wyllie, Susan, Fairlamb, Alan H., Boutet-Robinet, Élisa, Corvaisier, Sophie, Since, Marc, Malzert-Fréon, Aurélie, Destere, Alexandre, Mazier, Dominique, Rathelot, Pascal, Courtioux, Bertrand, Azas, Nadine, Verhaeghe, Pierre, and Vanelle, Patrice

Published
2020
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6. Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition

Author

Wyllie, Susan, Brand, Stephen, Thomas, Michael, De Rycker, Manu, Chung, Chun-wa, Pena, Imanol, Bingham, Ryan P., Bueren-Calabuig, Juan A., Cantizani, Juan, Cebrian, David, Craggs, Peter D., Ferguson, Liam, Goswami, Panchali, Hobrath, Judith, Howe, Jonathan, Jeacock, Laura, Ko, Eun-Jung, Korczynska, Justyna, MacLean, Lorna, Manthri, Sujatha, Martinez, Maria S., Mata-Cantero, Lydia, Moniz, Sonia, Nühs, Andrea, Osuna-Cabello, Maria, Pinto, Erika, Riley, Jennifer, Robinson, Sharon, Rowland, Paul, Simeons, Frederick R. C., Shishikura, Yoko, Spinks, Daniel, Stojanovski, Laste, Thomas, John, Thompson, Stephen, Gaza, Elisabet Viayna, Wall, Richard J., Zuccotto, Fabio, Horn, David, Ferguson, Michael A. J., Fairlamb, Alan H., Fiandor, Jose M., Martin, Julio, Gray, David W., Miles, Timothy J., Gilbert, Ian H., Read, Kevin D., Marco, Maria, and Wyatt, Paul G.

Published
2019

7. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Author

Baragan˜a, Beatriz, Forte, Barbara, Choi, Ryan, Hewitt, Stephen Nakazawa, Bueren-Calabuig, Juan A., Pisco, Joa˜o Pedro, Peet, Caroline, Dranow, David M., Robinson, David A., Jansen, Chimed, Norcross, Neil R., Vinayak, Sumiti, Anderson, Mark, Brooks, Carrie F., Cooper, Caitlin A., Damerow, Sebastian, Delves, Michael, Dowers, Karen, Duffy, James, Edwards, Thomas E., Hallyburton, Irene, Horst, Benjamin G., Hulverson, Matthew A., Ferguson, Liam, Jiménez-Díaz, María Belén, Jumani, Rajiv S., Lorimer, Donald D., Love, Melissa S., Maher, Steven, Matthews, Holly, McNamara, Case W., Miller, Peter, O’Neill, Sandra, Ojo, Kayode K., Osuna-Cabello, Maria, Pinto, Erika, Post, John, Riley, Jennifer, Rottmann, Matthias, Sanz, Laura M., Scullion, Paul, Sharma, Arvind, Shepherd, Sharon M., Shishikura, Yoko, Simeons, Frederick R. C., Stebbins, Erin E., Stojanovski, Laste, Straschil, Ursula, Tamaki, Fabio K., Tamjar, Jevgenia, Torrie, Leah S., Vantaux, Amélie, Witkowski, Benoît, Wittlin, Sergio, Yogavel, Manickam, Zuccotto, Fabio, Angulo-Barturen, Iñigo, Sinden, Robert, Baum, Jake, Gamo, Francisco-Javier, Mäser, Pascal, Kyle, Dennis E., Winzeler, Elizabeth A., Myler, Peter J., Wyatt, Paul G., Floyd, David, Matthews, David, Sharma, Amit, Striepen, Boris, Huston, Christopher D., Gray, David W., Fairlamb, Alan H., Pisliakov, Andrei V., Walpole, Chris, Read, Kevin D., Van Voorhis, Wesley C., and Gilbert, Ian H.

Published
2019

8. Validation of Trypanosoma cruzi inactivation techniques for laboratory use.

Author

MacLean, Lorna M., Ariyanayagam, Mark, Sastry, Lalitha, Paterson, Christy, De Rycker, Manu, and Fairlamb, Alan H.

Subjects
TRYPANOSOMA cruzi, CHAGAS' disease, LIFE cycles (Biology), LABORATORY techniques, FREEZE-thaw cycles, PARASITIC diseases
Abstract

Trypanosoma cruzi (T. cruzi) is the causative agent of Chagas' disease, a parasitic infection responsible for significant morbidity and mortality in Latin America. The current treatments have many serious drawbacks and new drugs are urgently required. In the UK, T. cruzi is classified by the Advisory Committee on Dangerous Pathogens (ACDP) as a Hazard Group 3 organism and strict safety practices must be adhered to when handling this pathogen in the laboratory. Validated inactivation techniques are required for safe T. cruzi waste disposal and removal from Containment Level 3 (CL3) facilities for storage, transportation and experimental analysis. Here we assess three T. cruzi. inactivation methods. These include three freeze-thaw cycles, chemical inactivation with Virkon disinfectant, and air drying on Whatman FTA cards (A, B, C, Elute) and on a Mitra microsampling device. After each treatment parasite growth was monitored for 4–6 weeks by microscopic examination. Three freeze-thaw cycles were sufficient to inactivate all T. cruzi CLBrener Luc life cycle stages and Silvio x10/7 A1 large epimastigote cell pellets up to two grams wet weight. Virkon treatment for one hour inactivated T. cruzi Silvio x10/7 subclone A1 and CLBrener Luc both in whole blood and cell culture medium when incubated at a final concentration of 2.5% Virkon, or at ≥1% Virkon when in tenfold excess of sample volume. Air drying also inactivated T. cruzi CLBrener Luc spiked blood when dried on FTA A, B or Elute cards for ≥30 minutes and on a Mitra Microsampler for two hours. However, T. cruzi CLBrener Luc were not inactivated on FTA C cards when dried for up to two hours. These experimentally confirmed conditions provide three validated T. cruzi inactivation methods which can be applied to other related ACDP Hazard Group 2–3 kinetoplastid parasites. [ABSTRACT FROM AUTHOR]

Published
2024
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10. The Genome of the African Trypanosome Trypanosoma brucei

Author

Berriman, Matthew, Ghedin, Elodie, Hertz-Fowler, Christiane, Blandin, Gaëlle, Renauld, Hubert, Bartholomeu, Daniella C., Lennard, Nicola J., Caler, Elisabet, Hamlin, Nancy E., Haas, Brian, Böhme, Ulrike, Hannick, Linda, Aslett, Martin A., Shallom, Joshua, Marcello, Lucio, Hou, Lihua, Wickstead, Bill, Arrowsmith, Claire, Atkin, Rebecca J., Barron, Andrew J., Bringaud, Frederic, Brooks, Karen, Carrington, Mark, Cherevach, Inna, Chillingworth, Tracey-Jane, Churcher, Carol, Clark, Louise N., Corton, Craig H., Cronin, Ann, Davies, Rob M., Doggett, Jonathon, Djikeng, Appolinaire, Feldblyum, Tamara, Field, Mark C., Fraser, Audrey, Goodhead, Ian, Hance, Zahra, Harper, David, Harris, Barbara R., Hauser, Heidi, Hostetler, Jessica, Ivens, Al, Jagels, Kay, Johnson, David, Johnson, Justin, Jones, Kristine, Kerhornou, Arnaud X., Koo, Hean, Larke, Natasha, Landfear, Scott, Larkin, Christopher, Leech, Vanessa, Line, Alexandra, Lord, Angela, MacLeod, Annette, Mooney, Paul J., Moule, Sharon, Morgan, Gareth W., Mungall, Karen, Norbertczak, Halina, Ormond, Doug, Pai, Grace, Peacock, Chris S., Peterson, Jeremy, Quail, Michael A., Rabbinowitsch, Ester, Rajandream, Marie-Adele, Reitter, Chris, Salzberg, Steven L., Sanders, Mandy, Schobel, Seth, Sharp, Sarah, Simmonds, Mark, Simpson, Anjana J., Tallon, Luke, Tait, Andrew, Tivey, Adrian R., Van Aken, Susan, Walker, Danielle, Wanless, David, Wang, Shiliang, White, Brian, White, Owen, Whitehead, Sally, Woodward, John, Wortman, Jennifer, Adams, Mark D., Embley, T. Martin, Gull, Keith, Ullu, Elisabetta, Barry, J. David, Fairlamb, Alan H., Opperdoes, Fred, Barrell, Barclay G., Donelson, John E., Hall, Neil, Fraser, Claire M., Melville, Sara E., and El-Sayed, Najib M.

Published
2005

14. Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis

Author

Wyllie, Susan, Thomas, Michael, Patterson, Stephen, Crouch, Sabrinia, De Rycker, Manu, Lowe, Rhiannon, Gresham, Stephanie, Urbaniak, Michael D., Otto, Thomas D., Stojanovski, Laste, Simeons, Frederick R. C., Manthri, Sujatha, MacLean, Lorna M., Zuccotto, Fabio, Homeyer, Nadine, Pflaumer, Hannah, Boesche, Markus, Sastry, Lalitha, Connolly, Paul, Albrecht, Sebastian, Berriman, Matt, Drewes, Gerard, Gray, David W., Ghidelli-Disse, Sonja, Dixon, Susan, Fiandor, Jose M., Wyatt, Paul G., Ferguson, Michael A. J., Fairlamb, Alan H., Miles, Timothy J., Read, Kevin D., and Gilbert, Ian H.

Published
2018
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18. A novel multiple-stage antimalarial agent that inhibits protein synthesis

Author

Baragaña, Beatriz, Hallyburton, Irene, Lee, Marcus C. S., Norcross, Neil R., Grimaldi, Raffaella, Otto, Thomas D., Proto, William R., Blagborough, Andrew M., Meister, Stephan, Wirjanata, Grennady, Ruecker, Andrea, Upton, Leanna M., Abraham, Tara S., Almeida, Mariana J., Pradhan, Anupam, Porzelle, Achim, Martínez, María Santos, Bolscher, Judith M., Woodland, Andrew, Norval, Suzanne, Zuccotto, Fabio, Thomas, John, Simeons, Frederick, Stojanovski, Laste, Osuna-Cabello, Maria, Brock, Paddy M., Churcher, Tom S., Sala, Katarzyna A., Zakutansky, Sara E., Jiménez-Díaz, María Belén, Sanz, Laura Maria, Riley, Jennifer, Basak, Rajshekhar, Campbell, Michael, Avery, Vicky M., Sauerwein, Robert W., Dechering, Koen J., Noviyanti, Rintis, Campo, Brice, Frearson, Julie A., Angulo-Barturen, Iñigo, Ferrer-Bazaga, Santiago, Gamo, Francisco Javier, Wyatt, Paul G., Leroy, Didier, Siegl, Peter, Delves, Michael J., Kyle, Dennis E., Wittlin, Sergio, Marfurt, Jutta, Price, Ric N., Sinden, Robert E., Winzeler, Elizabeth A., Charman, Susan A., Bebrevska, Lidiya, Gray, David W., Campbell, Simon, Fairlamb, Alan H., Willis, Paul A., Rayner, Julian C., Fidock, David A., Read, Kevin D., and Gilbert, Ian H.

Subjects
Antimalarials -- Product development, Protein synthesis -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

There is an urgent need for new drugs to treat malaria, with broad therapeutic potential and novel modes of action, to widen the scope of treatment and to overcome emerging drug resistance. Here we describe the discovery of DDD107498, a compound with a potent and novel spectrum of antimalarial activity against multiple life-cycle stages of the Plasmodium parasite, with good pharmacokinetic properties and an acceptable safety profile. DDD107498 demonstrates potential to address a variety of clinical needs, including single-dose treatment, transmission blocking and chemoprotection. DDD107498 was developed from a screening programme against blood-stage malaria parasites; its molecular target has been identified as translation elongation factor 2 (eEF2), which is responsible for the GTP-dependent translocation of the ribosome along messenger RNA, and is essential for protein synthesis. This discovery of eEF2 as a viable antimalarial drug target opens up new possibilities for drug discovery., Author(s): Beatriz Baragaña [1]; Irene Hallyburton [1]; Marcus C. S. Lee [2]; Neil R. Norcross [1]; Raffaella Grimaldi [1]; Thomas D. Otto [3]; William R. Proto [3]; Andrew M. Blagborough [...]

Published
2015
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23. 8-Methoxy-naphtho[2,3-b]thiophen-4,9-quinone, a non-competitive inhibitor of trypanothione reductase

Author

Zani Carlos L and Fairlamb Alan H

Subjects
trypanothione reductase, Trypanosoma cruzi, Leishmania, enzyme inhibitors, naphthoquinone, Microbiology, QR1-502, Infectious and parasitic diseases, RC109-216
Abstract

The enzyme trypanothione reductase is a recognised drug target in trypanosomatids and has been used in the search of new compounds with potential activity against diseases such as leishmaniasis, Chagas disease and African trypanosomiasis. 8-Methoxy-naphtho [2,3-b] thiophen-4,9-quinone was selected in a screening of natural and synthetic compounds using an in vitro assay with the recombinant enzyme from Trypanosoma cruzi. Its mode of inhibition fits a non-competitive model with respect to the substrate (trypanothione) and to the co-factor (NADPH), with Ki-values of 5 and 3.6 µM, respectively. When tested against human glutathione reductase, this compound did not display any significant inhibition at 100 µM, indicating a good selectivity against the parasite enzyme.

Published
2003

26. TrypanoCyc: a community-led biochemical pathways database for Trypanosoma brucei

Author

Shameer, Sanu, Logan-Klumpler, Flora J., Vinson, Florence, Cottret, Ludovic, Merlet, Benjamin, Achcar, Fiona, Boshart, Michael, Berriman, Matthew, Breitling, Rainer, Bringaud, Frédéric, Bütikofer, Peter, Cattanach, Amy M., Bannerman-Chukualim, Bridget, Creek, Darren J., Crouch, Kathryn, de Koning, Harry P., Denise, Hubert, Ebikeme, Charles, Fairlamb, Alan H., Ferguson, Michael A. J., Ginger, Michael L., Hertz-Fowler, Christiane, Kerkhoven, Eduard J., Mäser, Pascal, Michels, Paul A. M., Nayak, Archana, Nes, David W., Nolan, Derek P., Olsen, Christian, Silva-Franco, Fatima, Smith, Terry K., Taylor, Martin C., Tielens, Aloysius G. M., Urbaniak, Michael D., van Hellemond, Jaap J., Vincent, Isabel M., Wilkinson, Shane R., Wyllie, Susan, Opperdoes, Fred R., Barrett, Michael P., and Jourdan, Fabien

Published
2015
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32. N-myristoyltransferase inhibitors as new leads to treat sleeping sickness

Author

Frearson, Julie A., Brand, Stephen, McElroy, Stuart P., Cleghorn, Laura A.T., Smid, Ondrej, Stojanovski, Laste, Price, Helen P., Guther, M. Lucia S., Torrie, Leah S., Robinson, David A., Hallyburton, Irene, Mpamhanga, Chidochangu P., Brannigan, James A., Wilkinson, Anthony J., Hodgkinson, Michael, Hui, Raymond, Qiu, Wei, Raimi, Olawale G., van Aalten, Daan M.F., Brenk, Ruth, Gilbert, Ian H., Read, Kevin D., Fairlamb, Alan H., Ferguson, Michael A.J., Smith, Deborah F., and Wyatt, Paul G.

Subjects
Post-translational modification -- Research, Transferases -- Physiological aspects -- Control -- Research, Enzyme inhibitors -- Usage -- Health aspects, Trypanosomiasis -- Genetic aspects -- Care and treatment -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

African sleeping sickness or human African trypanosomiasis, caused by Trypanosoma bruceispp., is responsible for ~30,000 deaths each year. Available treatments for this disease are poor, with unacceptable efficacy and safety profiles, particularly in the late stage of the disease when the parasite has infected the central nervous system. Here we report the validation of a molecular target and the discovery of associated lead compounds with the potential to address this lack of suitable treatments. Inhibition of this target--T. brucei N-myristoyltransferase--leads to rapid killing of trypanosomes both in vitro and in vivo and cures trypanosomiasis in mice. These high-affinity inhibitors bind into the peptide substrate pocket of the enzyme and inhibit protein N-myristoylation in trypanosomes. The compounds identified have promising pharmaceutical properties and represent an opportunity to develop oral drugs to treat this devastating disease. Our studies validate T. brucei N-myristoyltransferase as a promising therapeutic target for human African trypanosomiasis., Protein N-myristoylation is a ubiquitous eukaryotic co- and posttranslational modification and is required for the membrane targeting and biological activity of many important proteins (1,2). The N-myristoylation reaction--the transfer of [...]

Published
2010
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34. Characterisation of a putative glutamate 5‐kinase from Leishmania donovani

Author

Sienkiewicz, Natasha, Ong, Han B., and Fairlamb, Alan H.

Subjects
Proline, Genetic Vectors, Protozoan Proteins, Gene Expression, Glutamic Acid, drug target, Substrate Specificity, inhibitors, Escherichia coli, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Cloning, Molecular, biochemical pathway, Phylogeny, Leishmania, Aspartic Acid, Sequence Homology, Amino Acid, Genetic Complementation Test, Original Articles, Phosphotransferases (Carboxyl Group Acceptor), Recombinant Proteins, Kinetics, Biocatalysis, proline biosynthesis, Thermodynamics, Original Article, Protein Multimerization, Sequence Alignment, Leishmania donovani, Protein Binding
Abstract

Previous metabolic studies have demonstrated that leishmania parasites are able to synthesise proline from glutamic acid and threonine from aspartic acid. The first committed step in both biosynthetic pathways involves an amino acid kinase, either a glutamate 5‐kinase (G5K; http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/2/11.html) or an aspartokinase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/2/4.html). Bioinformatic analysis of multiple leishmania genomes identifies a single amino acid‐kinase gene (LdBPK 262740.1) variously annotated as either a putative glutamate or aspartate kinase. To establish the catalytic function of this Leishmania donovani gene product, we have determined the physical and kinetic properties of the recombinant enzyme purified from Escherichia coli. The findings indicate that the enzyme is a bona fide G5K with no activity as an aspartokinase. Tetrameric G5K displays kinetic behaviour similar to its bacterial orthologues and is allosterically regulated by proline, the end product of the pathway. The structure‐activity relationships of proline analogues as inhibitors are broadly similar to the bacterial enzyme. However, unlike G5K from E. coli, leishmania G5K lacks a C‐terminal PUA (pseudouridine synthase and archaeosine transglycosylase) domain and does not undergo higher oligomerisation in the presence of proline. Gene replacement studies are suggestive, but not conclusive that G5K is essential. Enzymes Glutamate 5‐kinase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/2/11.html); aspartokinase (http://www.chem.qmul.ac.uk/iubmb/enzyme/EC2/7/2/4.html).

Published
2018

37. Genome sequence of the human malaria parasite Plasmodium falciparum

Author

Gardner, Malcolm J., Hall, Neil, Fung, Eula, White, Owen, Berriman, Matthew, Hyman, Richard W., Carlton, Jane M., Pain, Arnab, Nelson, Karen E., Bowman, Sharen, Paulsen, Ian T., James, Keith, Eisen, Jonathan A., Rutherford, Kim, Salzberg, Steven L., Craig, Alister, Kyes, Sue, Chan, Man-Suen, Nene, Vishvanath, Shallom, Shamira J., Suh, Bernard, Peterson, Jeremy, Angiuoli, Sam, Pertea, Mihaela, Allen, Jonathan, Selengut, Jeremy, Haft, Daniel, Mather, Michael W., Vaidya, Akhil B., Martin, David M. A., Fairlamb, Alan H., Fraunholz, Martin J., Roos, David S., Ralph, Stuart A., McFadden, Geoffrey I., Cummings, Leda M., Subramanian, G. Mani, Mungall, Chris, Venter, J. Craig, Carucci, Daniel J., Hoffman, Stephen L., Newbold, Chris, Davis, Ronald W., Fraser, Claire M., and Barrell, Bart

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Malcolm J. Gardner (corresponding author) [1]; Neil Hall [2]; Eula Fung [3]; Owen White [1]; Matthew Berriman [2]; Richard W. Hyman [3]; Jane M. Carlton [1]; Arnab Pain [2]; [...]

Published
2002
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48. Corrigendum: A novel multiple-stage antimalarial agent that inhibits protein synthesis

Author

Baragaa, Beatriz, Hallyburton, Irene, Lee, Marcus C. S., Norcross, Neil R., Grimaldi, Raffaella, Otto, Thomas D., Proto, William R., Blagborough, Andrew M., Meister, Stephan, Wirjanata, Grennady, Ruecker, Andrea, Upton, Leanna M., Abraham, Tara S., Almeida, Mariana J., Pradhan, Anupam, Porzelle, Achim, Martnez, Mara Santos, Bolscher, Judith M., Woodland, Andrew, Luksch, Torsten, Norval, Suzanne, Zuccotto, Fabio, Thomas, John, Simeons, Frederick, Stojanovski, Laste, Osuna-Cabello, Maria, Brock, Paddy M., Churcher, Tom S., Sala, Katarzyna A., Zakutansky, Sara E., Jimnez-Daz, Mara Beln, Sanz, Laura Maria, Riley, Jennifer, Basak, Rajshekhar, Campbell, Michael, Avery, Vicky M., Sauerwein, Robert W., Dechering, Koen J., Noviyanti, Rintis, Campo, Brice, Frearson, Julie A., Angulo-Barturen, Iigo, Ferrer-Bazaga, Santiago, Gamo, Francisco Javier, Wyatt, Paul G., Leroy, Didier, Siegl, Peter, Delves, Michael J., Kyle, Dennis E., Wittlin, Sergio, Marfurt, Jutta, Price, Ric N., Sinden, Robert E., Winzeler, Elizabeth A., Charman, Susan A., Bebrevska, Lidiya, Gray, David W., Campbell, Simon, Fairlamb, Alan H., Willis, Paul A., Rayner, Julian C., Fidock, David A., Read, Kevin D., and Gilbert, Ian H.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Beatriz Baragaa; Irene Hallyburton; Marcus C. S. Lee; Neil R. Norcross; Raffaella Grimaldi; Thomas D. Otto; William R. Proto; Andrew M. Blagborough; Stephan Meister; Grennady Wirjanata; Andrea Ruecker; Leanna [...]

Published
2016
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49. Lysyl-tRNA synthetase as a drug target in malaria and cryptosporidiosis

Author

Baragaña, Beatriz, Forte, Barbara, Choi, Ryan, Nakazawa Hewitt, Stephen, Bueren-Calabuig, Juan A., Pisco, João Pedro, Peet, Caroline, Dranow, David M., Robinson, David A., Jansen, Chimed, Norcross, Neil R., Vinayak, Sumiti, Anderson, Mark, Brooks, Carrie F., Cooper, Caitlin A., Damerow, Sebastian, Delves, Michael, Dowers, Karen, Duffy, James, Edwards, Thomas E., Hallyburton, Irene, Horst, Benjamin G., Hulverson, Matthew A., Ferguson, Liam, Jiménez-Díaz, María Belén, Jumani, Rajiv S., Lorimer, Donald D., Love, Melissa S., Maher, Steven, Matthews, Holly, McNamara, Case W., Miller, Peter, O’Neill, Sandra, Ojo, Kayode K., Osuna-Cabello, Maria, Pinto, Erika, Post, John, Riley, Jennifer, Rottmann, Matthias, Sanz, Laura M., Scullion, Paul, Sharma, Arvind, Shepherd, Sharon M., Shishikura, Yoko, Simeons, Frederick R. C., Stebbins, Erin E., Stojanovski, Laste, Straschil, Ursula, Tamaki, Fabio K., Tamjar, Jevgenia, Torrie, Leah S., Vantaux, Amélie, Witkowski, Benoît, Wittlin, Sergio, Yogavel, Manickam, Zuccotto, Fabio, Angulo-Barturen, Iñigo, Sinden, Robert, Baum, Jake, Gamo, Francisco-Javier, Mäser, Pascal, Kyle, Dennis E., Winzeler, Elizabeth A., Myler, Peter J., Wyatt, Paul G., Floyd, David, Matthews, David, Sharma, Amit, Striepen, Boris, Huston, Christopher D., Gray, David W., Fairlamb, Alan H., Pisliakov, Andrei V., Walpole, Chris, Read, Kevin D., Van Voorhis, Wesley C., Gilbert, Ian H., University of Dundee, Seattle Structural Genomics Center for Infectious Disease (SSGCID), University of Washington [Seattle], Beryllium Discovery Corp. [Bainbridge Island, WA], University of Georgia [USA], Imperial College London, Medicines for Malaria Venture [Geneva] (MMV), The Art of Discovery [Bizkaia, Spain] (TAD), University of Vermont [Burlington], Scripps Research Institute, Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), GlaxoSmithKline (GSK), International Centre for Genetic Engineering and Biotechnology [New Delhi] (ICGEB), Malaria Molecular Epidemiology, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of California [San Diego] (UC San Diego), University of California, Seattle Children's Research Institute [Seattle, WA, USA], University of Toronto, University of Pennsylvania [Philadelphia], McGill University = Université McGill [Montréal, Canada], This work was supported by the Bill and Melinda Gates Foundation through Grant OPP1032548 to the Structure-Guided Drug Discovery Coalition and OPP1134302 (to B.S.). This work was also supported in part from federal funds, from the NIH/National Institute of Allergy and Infectious Diseases Grant R21AI123690 (to K.K.O.) and Contracts HHSN272201200025C and HHSN272201700059C (to P.J.M.), Medicines for Malaria Venture (through access to assays to I.H.G. and through RD/08/2800 to J.B.), Wellcome Trust for support of the X-ray Crystallography Facility 094090, IT support Grant 105021 (to I.H.G.), and Institutional Strategic Support Fund 204816 (to A.V.P.), all at the University of Dundee and for Investigator Award 100993 (to J.B.)., We thank the European Synchrotron Radiation Facility for beamtime, highlighting the staff of beamlines BM14 and ID29, Diamond Light Source for beamtime (proposal mx10071), the staff of beamline I24 for assistance with crystal testing and data collection, the entire Seattle Structural Genomics Center for Infectious Disease team, the Division of Biological Chemistry and Drug Discovery Protein Production Team, GlaxoSmithKline for the Tres Campos Antimalarial screening set, the Scottish Blood Transfusion Centre (Ninewells Hospital, Dundee) for providing human erythrocytes, Christoph Fischli and Sibylle Sax at the SwissTPH for technical assistance with the SCID mouse model, and and Anja Schäfer for technical assistance with the in vitro antimalarial activity testing. The Art of Discovery thanks Dr. Cristina Eguizabal and the Basque Center of Transfusion and Human Tissues (Galdakao, Spain) and the Bank of Blood and Tissues (Barcelona, Spain) for providing human blood. The University of California, San Diego thanks Jenya Antonova-Koch for help.

Subjects
Lysine-tRNA Ligase, tRNA synthetase, Plasmodium falciparum, Protozoan Proteins, malaria, Mice, SCID, Microbiology, parasitic diseases, Animals, Humans, MESH: Animals, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Enzyme Inhibitors, Malaria, Falciparum, MESH: Mice, SCID, MESH: Protozoan Proteins, MESH: Plasmodium falciparum, Cryptosporidium parvum, MESH: Humans, cryptosporidiosis, MESH: Lysine-tRNA Ligase, MESH: Malaria, Falciparum, MESH: Cryptosporidiosis, Biological Sciences, Chemistry, Disease Models, Animal, MESH: Enzyme Inhibitors, Physical Sciences, MESH: Cryptosporidium parvum, MESH: Disease Models, Animal
Abstract

Significance Malaria and cryptosporidiosis are major burdens to both global health and economic development in many countries. Malaria caused >400,000 deaths in 2017, and cryptosporidiosis is estimated to cause >200,000 deaths a year. The spread of drug resistance is a growing concern for malaria treatment, and there is no effective treatment for malnourished or immunocompromised children infected with Cryptosporidium. New treatments with novel mechanisms of action are needed for both diseases. We present a selective inhibitor of both Plasmodium and Cryptosporidium lysyl-tRNA synthetase capable of clearing parasites from mouse models of malaria and cryptosporidiosis infection. This provides very strong validation of lysyl-tRNA synthetase as a drug target in these organisms and a lead for further drug discovery., Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stage Plasmodium falciparum and Cryptosporidium parvum in cell-culture studies. Target deconvolution in P. falciparum has shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of both PfKRS1 and C. parvum KRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90 = 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology between PfKRS1 and CpKRS. This series of compounds inhibit CpKRS and C. parvum and Cryptosporidium hominis in culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds for PfKRS1 and CpKRS vs. (human) HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.

Published
2019

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