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Your search keyword '"Harrison, Justin R."' showing total 8 results
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8 results on '"Harrison, Justin R."'

2. Repositioning of a Diaminothiazole Series Confirmed to Target the Cyclin-Dependent Kinase CRK12 for Use in the Treatment of African Animal Trypanosomiasis

Author

Smith, Alasdair, primary, Wall, Richard J., additional, Patterson, Stephen, additional, Rowan, Tim, additional, Rico Vidal, Eva, additional, Stojanovski, Laste, additional, Huggett, Margaret, additional, Hampton, Shahienaz E., additional, Thomas, Michael G., additional, Corpas Lopez, Victoriano, additional, Gillingwater, Kirsten, additional, Duke, Jeff, additional, Napier, Grant, additional, Peter, Rose, additional, Vitouley, Hervé S., additional, Harrison, Justin R., additional, Milne, Rachel, additional, Jeacock, Laura, additional, Baker, Nicola, additional, Davis, Susan H., additional, Simeons, Frederick, additional, Riley, Jennifer, additional, Horn, David, additional, Brun, Reto, additional, Zuccotto, Fabio, additional, Witty, Michael J, additional, Wyllie, Susan, additional, Read, Kevin D., additional, and Gilbert, Ian H., additional

Published
2022
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3. 2-Mercapto-Quinazolinones as Inhibitors of Type II NADH Dehydrogenase and Mycobacterium tuberculosis: Structure–Activity Relationships, Mechanism of Action and Absorption, Distribution, Metabolism, and Excretion Characterization

Author

Murugesan, Dinakaran, Ray, Peter C., Bayliss, Tracy, Prosser, Gareth A., Harrison, Justin R., Green, Kirsteen, Soares de Melo, Candice, Feng, Tzu-Shean, Street, Leslie J., Chibale, Kelly, Warner, Digby F., Mizrahi, Valerie, Epemolu, Ola, Scullion, Paul, Ellis, Lucy, Riley, Jennifer, Shishikura, Yoko, Ferguson, Liam, Osuna-Cabello, Maria, Read, Kevin D., Green, Simon R., Lamprecht, Dirk A., Finin, Peter M., Steyn, Adrie J. C., Ioerger, Thomas R., Sacchettini, Jim, Rhee, Kyu Y., Arora, Kriti, Barry, Clifton E., Wyatt, Paul G., and Boshoff, Helena I. M.

Subjects
structure−activity relationship, Structure-Activity Relationship, mercapto-quinazolinones, Molecular Structure, type II NADH dehydrogenase, NADH Dehydrogenase, Mycobacterium tuberculosis, Article, small molecule NDH-2 inhibitors, respiration, Quinazolinones
Abstract

Mycobacterium tuberculosis ( MTb) possesses two nonproton pumping type II NADH dehydrogenase (NDH-2) enzymes which are predicted to be jointly essential for respiratory metabolism. Furthermore, the structure of a closely related bacterial NDH-2 has been reported recently, allowing for the structure-based design of small-molecule inhibitors. Herein, we disclose MTb whole-cell structure-activity relationships (SARs) for a series of 2-mercapto-quinazolinones which target the ndh encoded NDH-2 with nanomolar potencies. The compounds were inactivated by glutathione-dependent adduct formation as well as quinazolinone oxidation in microsomes. Pharmacokinetic studies demonstrated modest bioavailability and compound exposures. Resistance to the compounds in MTb was conferred by promoter mutations in the alternative nonessential NDH-2 encoded by ndhA in MTb. Bioenergetic analyses revealed a decrease in oxygen consumption rates in response to inhibitor in cells in which membrane potential was uncoupled from ATP production, while inverted membrane vesicles showed mercapto-quinazolinone-dependent inhibition of ATP production when NADH was the electron donor to the respiratory chain. Enzyme kinetic studies further demonstrated noncompetitive inhibition, suggesting binding of this scaffold to an allosteric site. In summary, while the initial MTb SAR showed limited improvement in potency, these results, combined with structural information on the bacterial protein, will aid in the future discovery of new and improved NDH-2 inhibitors.

Published
2018

5. Discovery and Optimization of a Compound Series Active against Trypanosoma cruzi, the Causative Agent of Chagas Disease

Author

Harrison, Justin R., primary, Sarkar, Sandipan, additional, Hampton, Shahienaz, additional, Riley, Jennifer, additional, Stojanovski, Laste, additional, Sahlberg, Christer, additional, Appelqvist, Pia, additional, Erath, Jessey, additional, Mathan, Vinodhini, additional, Rodriguez, Ana, additional, Kaiser, Marcel, additional, Pacanowska, Dolores Gonzalez, additional, Read, Kevin D., additional, Johansson, Nils Gunnar, additional, and Gilbert, Ian H., additional

Published
2020
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6. A Molecular Hybridization Approach for the Design of Potent, Highly Selective, and Brain-Penetrant N-Myristoyltransferase Inhibitors

Author

Harrison, Justin R., primary, Brand, Stephen, additional, Smith, Victoria, additional, Robinson, David A., additional, Thompson, Stephen, additional, Smith, Alasdair, additional, Davies, Kenneth, additional, Mok, Ngai, additional, Torrie, Leah S., additional, Collie, Iain, additional, Hallyburton, Irene, additional, Norval, Suzanne, additional, Simeons, Frederick R. C., additional, Stojanovski, Laste, additional, Frearson, Julie A., additional, Brenk, Ruth, additional, Wyatt, Paul G., additional, Gilbert, Ian H., additional, and Read, Kevin D., additional

Published
2018
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8. N-Myristoyltransferase Is a Cell Wall Target in Aspergillus fumigatus

Author

Fang, Wenxia, primary, Robinson, David A., additional, Raimi, Olawale G., additional, Blair, David E., additional, Harrison, Justin R., additional, Lockhart, Deborah E. A., additional, Torrie, Leah S., additional, Ruda, Gian Filippo, additional, Wyatt, Paul G., additional, Gilbert, Ian H., additional, and van Aalten, Daan M. F., additional

Published
2015
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