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15 results on '"Sanz, Olalla"'

1. Exploration of the P1 residue in 3CL protease inhibitors leading to the discovery of a 2-tetrahydrofuran P1 replacement

Author

Barton, Linda S., Callahan, James F., Cantizani, Juan, Concha, Nestor O., Cotillo Torrejon, Ignacio, Goodwin, Nicole C., Joshi-Pangu, Amruta, Kiesow, Terry J., McAtee, Jeff J., Mellinger, Mark, Nixon, Christopher J., Padrón-Barthe, Laura, Patterson, Jaclyn R., Pearson, Neil D., Pouliot, Jeffrey J., Rendina, Alan R., Buitrago Santanilla, Alexander, Schneck, Jessica L., Sanz, Olalla, Thalji, Reema K., Ward, Paris, Williams, Shawn P., and King, Bryan W.

Published
2024
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4. Exploration of the P1 Residue in CL Protease Inhibitors Leading to the Discovery of a Novel 2-Tetrahydrofuran P1 Replacement

Author

Barton, Linda, primary, Callahan, James F., additional, Cantizani, Juan, additional, Concha, Nestor O., additional, Torrejon, Ignacio Cotillo, additional, Goodwin, Nicole C., additional, Joshi-Pangu, Amruta, additional, Kiesow, Terry J., additional, McAtee, Jeff J., additional, Mellinger, Mark, additional, Nixon, Christopher J., additional, Padrón, Laura, additional, Patterson, Jaclyn R., additional, Pearson, Neil D., additional, Pouliot, Jeffrey J., additional, Rendina, Alan R., additional, Santanilla, Alexander Buitrago, additional, Schneck, Jessica L., additional, Sanz, Olalla, additional, Thalji, Reema K., additional, Ward, Paris, additional, Williams, Shawn P., additional, and King, Bryan W., additional

Published
2023
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5. 1,3-Diarylpyrazolyl-acylsulfonamides Target HadAB/BC Complex in Mycobacterium tuberculosis

Author

Singh, Vinayak, primary, Grzegorzewicz, Anna E., additional, Fienberg, Stephen, additional, Müller, Rudolf, additional, Khonde, Lutete Peguy, additional, Sanz, Olalla, additional, Alfonso, Salvatore, additional, Urones, Beatriz, additional, Drewes, Gerard, additional, Bantscheff, Marcus, additional, Ghidelli-Disse, Sonja, additional, Ioerger, Thomas R., additional, Angala, Bhanupriya, additional, Liu, Jiuyu, additional, Lee, Richard E., additional, Sacchettini, James C., additional, Krieger, Inna V., additional, Jackson, Mary, additional, Chibale, Kelly, additional, and Ghorpade, Sandeep R., additional

Published
2022
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6. GSK2556286 Is a Novel Antitubercular Drug Candidate Effective In Vivo with the Potential To Shorten Tuberculosis Treatment

Author

Nuermberger, Eric L., primary, Martínez-Martínez, Maria Santos, additional, Sanz, Olalla, additional, Urones, Beatriz, additional, Esquivias, Jorge, additional, Soni, Heena, additional, Tasneen, Rokeya, additional, Tyagi, Sandeep, additional, Li, Si-Yang, additional, Converse, Paul J., additional, Boshoff, Helena I., additional, Robertson, Gregory T., additional, Besra, Gurdyal S., additional, Abrahams, Katherine A., additional, Upton, Anna M., additional, Mdluli, Khisimuzi, additional, Boyle, Gary W., additional, Turner, Sam, additional, Fotouhi, Nader, additional, Cammack, Nicholas C., additional, Siles, Juan Miguel, additional, Alonso, Marta, additional, Escribano, Jaime, additional, Lelievre, Joel, additional, Rullas-Trincado, Joaquin, additional, Pérez-Herrán, Esther, additional, Bates, Robert H., additional, Maher-Edwards, Gareth, additional, Barros, David, additional, Ballell, Lluís, additional, and Jiménez, Elena, additional

Published
2022
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7. Ca2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG

Author

Balestra, Aurélia C., Koussis, Konstantinos, Klages, Natacha, Howell, Steven A., Flynn, Helen R., Bantscheff, Marcus, Pasquarello, Carla, Perrin, Abigail J., Brusini, Lorenzo, Arboit, Patrizia, Sanz, Olalla, Castaño, Laura Peces-Barba, Withers-Martinez, Chrislaine, Hainard, Alexandre, Ghidelli-Disse, Sonja, Snijders, Ambrosius P., Baker, David A., Blackman, Michael J., and Brochet, Mathieu

Subjects
Plasmodium berghei, Protozoan Proteins, SciAdv r-articles, Membrane Proteins, Cell Biology, Microbiology, Gametogenesis, Malaria, parasitic diseases, cardiovascular system, Animals, Calcium, Parasites, Calcium Channels, Research Articles, Research Article
Abstract

A membrane protein interacts with PKG and regulates calcium signals at multiple lifecycle stages in malaria parasites., Calcium signaling regulated by the cGMP-dependent protein kinase (PKG) controls key life cycle transitions in the malaria parasite. However, how calcium is mobilized from intracellular stores in the absence of canonical calcium channels in Plasmodium is unknown. Here, we identify a multipass membrane protein, ICM1, with homology to transporters and calcium channels that is tightly associated with PKG in both asexual blood stages and transmission stages. Phosphoproteomic analyses reveal multiple ICM1 phosphorylation events dependent on PKG activity. Stage-specific depletion of Plasmodium berghei ICM1 prevents gametogenesis due to a block in intracellular calcium mobilization, while conditional loss of Plasmodium falciparum ICM1 is detrimental for the parasite resulting in severely reduced calcium mobilization, defective egress, and lack of invasion. Our findings suggest that ICM1 is a key missing link in transducing PKG-dependent signals and provide previously unknown insights into atypical calcium homeostasis in malaria parasites essential for pathology and disease transmission.

Published
2021

8. Ca 2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG

Author

Balestra, Aurélia C., primary, Koussis, Konstantinos, additional, Klages, Natacha, additional, Howell, Steven A., additional, Flynn, Helen R., additional, Bantscheff, Marcus, additional, Pasquarello, Carla, additional, Perrin, Abigail J., additional, Brusini, Lorenzo, additional, Arboit, Patrizia, additional, Sanz, Olalla, additional, Castaño, Laura Peces-Barba, additional, Withers-Martinez, Chrislaine, additional, Hainard, Alexandre, additional, Ghidelli-Disse, Sonja, additional, Snijders, Ambrosius P., additional, Baker, David A., additional, Blackman, Michael J., additional, and Brochet, Mathieu, additional

Published
2021
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9. A multipass membrane protein interacts with the cGMP-dependent protein kinase to regulate critical calcium signals in malaria parasites

Author

Balestra, Aurélia C., primary, Koussis, Konstantinos, additional, Klages, Natacha, additional, Howell, Steven A., additional, Flynn, Helen R., additional, Bantscheff, Marcus, additional, Pasquarello, Carla, additional, Perrin, Abigail J., additional, Brusini, Lorenzo, additional, Arboit, Patrizia, additional, Sanz, Olalla, additional, Castaño, Laura Peces-Barba, additional, Withers-Martinez, Chrislaine, additional, Hainard, Alexandre, additional, Ghidelli-Disse, Sonja, additional, Snijders, Ambrosius P., additional, Baker, David A., additional, Blackman, Michael J., additional, and Brochet, Mathieu, additional

Published
2020
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10. Inhibition of Resistance-Refractory P. falciparum Kinase PKG Delivers Prophylactic, Blood Stage, and Transmission-Blocking Antiplasmodial Activity

Author

Vanaerschot, Manu, primary, Murithi, James M., additional, Pasaje, Charisse Flerida A., additional, Ghidelli-Disse, Sonja, additional, Dwomoh, Louis, additional, Bird, Megan, additional, Spottiswoode, Natasha, additional, Mittal, Nimisha, additional, Arendse, Lauren B., additional, Owen, Edward S., additional, Wicht, Kathryn J., additional, Siciliano, Giulia, additional, Bösche, Markus, additional, Yeo, Tomas, additional, Kumar, T.R. Santha, additional, Mok, Sachel, additional, Carpenter, Emma F., additional, Giddins, Marla J., additional, Sanz, Olalla, additional, Ottilie, Sabine, additional, Alano, Pietro, additional, Chibale, Kelly, additional, Llinás, Manuel, additional, Uhlemann, Anne-Catrin, additional, Delves, Michael, additional, Tobin, Andrew B., additional, Doerig, Christian, additional, Winzeler, Elizabeth A., additional, Lee, Marcus C.S., additional, Niles, Jacquin C., additional, and Fidock, David A., additional

Published
2020
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11. Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

Author

Wilson, Colin R, Gessner, Richard K, Moosa, Atica, Seldon, Ronnett, Warner, Digby F, Mizrahi, Valerie, Soares de Melo, Candice, Simelane, Sandile B, Nchinda, Aloysius, Abay, Efrem, Taylor, Dale, Njoroge, Mathew, Brunschwig, Christel, Lawrence, Nina, Boshoff, Helena I M, Barry, Clifton E, Sirgel, Frederick A, van Helden, Paul, Harris, C John, Gordon, Richard, Ghidelli-Disse, Sonja, Pflaumer, Hannah, Boesche, Markus, Drewes, Gerard, Sanz, Olalla, Santos, Gracia, Rebollo-Lopez, Maria José, Urones, Beatriz, Selenski, Carolyn, Lafuente-Monasterio, Maria Jose, Axtman, Matthew, Lelièvre, Joël, Ballell, Lluis, Mueller, Rudolf, Street, Leslie J, Ghorpade, Sandeep R, and Chibale, Kelly

Subjects
Male, Proteomics, Antitubercular Agents, Administration, Oral, Blood Proteins, Mycobacterium tuberculosis, Article, High-Throughput Screening Assays, Mice, Inbred C57BL, Small Molecule Libraries, Structure-Activity Relationship, Pyrimidines, Drug Stability, Microsomes, Liver, Animals, Humans
Abstract

A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis (Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1 complex, disruption of cell-wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure-activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.

Published
2017

12. Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis

Author

Park, Yumi, primary, Pacitto, Angela, additional, Bayliss, Tracy, additional, Cleghorn, Laura A. T., additional, Wang, Zhe, additional, Hartman, Travis, additional, Arora, Kriti, additional, Ioerger, Thomas R., additional, Sacchettini, Jim, additional, Rizzi, Menico, additional, Donini, Stefano, additional, Blundell, Tom L., additional, Ascher, David B., additional, Rhee, Kyu, additional, Breda, Ardala, additional, Zhou, Nian, additional, Dartois, Veronique, additional, Jonnala, Surendranadha Reddy, additional, Via, Laura E., additional, Mizrahi, Valerie, additional, Epemolu, Ola, additional, Stojanovski, Laste, additional, Simeons, Fred, additional, Osuna-Cabello, Maria, additional, Ellis, Lucy, additional, MacKenzie, Claire J., additional, Smith, Alasdair R. C., additional, Davis, Susan H., additional, Murugesan, Dinakaran, additional, Buchanan, Kirsteen I., additional, Turner, Penelope A., additional, Huggett, Margaret, additional, Zuccotto, Fabio, additional, Rebollo-Lopez, Maria Jose, additional, Lafuente-Monasterio, Maria Jose, additional, Sanz, Olalla, additional, Diaz, Gracia Santos, additional, Lelièvre, Joël, additional, Ballell, Lluis, additional, Selenski, Carolyn, additional, Axtman, Matthew, additional, Ghidelli-Disse, Sonja, additional, Pflaumer, Hannah, additional, Bösche, Markus, additional, Drewes, Gerard, additional, Freiberg, Gail M., additional, Kurnick, Matthew D., additional, Srikumaran, Myron, additional, Kempf, Dale J., additional, Green, Simon R., additional, Ray, Peter C., additional, Read, Kevin, additional, Wyatt, Paul, additional, Barry, Clifton E., additional, and Boshoff, Helena I., additional

Published
2016
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13. Novel Antitubercular 6-Dialkylaminopyrimidine Carboxamides from Phenotypic Whole-Cell High Throughput Screening of a SoftFocus Library: Structure–Activity Relationship and Target Identification Studies

Author

Wilson, Colin R., Gessner, Richard K., Moosa, Atica, Seldon, Ronnett, Warner, Digby F., Mizrahi, Valerie, Soares de Melo, Candice, Simelane, Sandile B., Nchinda, Aloysius, Abay, Efrem, Taylor, Dale, Njoroge, Mathew, Brunschwig, Christel, Lawrence, Nina, Boshoff, Helena I. M., Barry, Clifton E., Sirgel, Frederick A., van Helden, Paul, Harris, C. John, Gordon, Richard, Ghidelli-Disse, Sonja, Pflaumer, Hannah, Boesche, Markus, Drewes, Gerard, Sanz, Olalla, Santos, Gracia, Rebollo-Lopez, Maria José, Urones, Beatriz, Selenski, Carolyn, Lafuente-Monasterio, Maria Jose, Axtman, Matthew, Lelièvre, Joël, Ballell, Lluis, Mueller, Rudolf, Street, Leslie J., Ghorpade, Sandeep R., and Chibale, Kelly

Abstract

A BioFocus DPI SoftFocus library of ∼35 000 compounds was screened against Mycobacterium tuberculosis(Mtb) in order to identify novel hits with antitubercular activity. The hits were evaluated in biology triage assays to exclude compounds suggested to function via frequently encountered promiscuous mechanisms of action including inhibition of the QcrB subunit of the cytochrome bc1complex, disruption of cell–wall homeostasis, and DNA damage. Among the hits that passed this screening cascade, a 6-dialkylaminopyrimidine carboxamide series was prioritized for hit to lead optimization. Compounds from this series were active against clinical Mtb strains, while no cross-resistance to conventional antituberculosis drugs was observed. This suggested a novel mechanism of action, which was confirmed by chemoproteomic analysis leading to the identification of BCG_3193 and BCG_3827 as putative targets of the series with unknown function. Initial structure–activity relationship studies have resulted in compounds with moderate to potent antitubercular activity and improved physicochemical properties.

Published
2024
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14. Ca2+ signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG.

Author

Balestra, Aurélia C., Koussis, Konstantinos, Klages, Natacha, Howell, Steven A., Flynn, Helen R., Bantscheff, Marcus, Pasquarello, Carla, Perrin, Abigail J., Brusini, Lorenzo, Arboit, Patrizia, Sanz, Olalla, Castaño, Laura Peces-Barba, Withers-Martinez, Chrislaine, Hainard, Alexandre, Ghidelli-Disse, Sonja, Snijders, Ambrosius P., Baker, David A., Blackman, Michael J., and Brochet, Mathieu

Subjects
*MEMBRANE proteins, *PLASMODIUM, *INTRACELLULAR calcium, *GAMETOGENESIS, *CALCIUM channels, *GREEN fluorescent protein, *RYANODINE receptors, *HEAT shock proteins
Abstract

The article presents a study related to calcium signals critical for egress and gametogenesis in malaria parasites depend on a multipass membrane protein that interacts with PKG. It mentions that calcium signaling regulated by the cGMP-dependent protein kinase (PKG) controls key life cycle transitions in the malaria parasite.

Published
2021
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15. Essential but Not Vulnerable: Indazole Sulfonamides Targeting Inosine Monophosphate Dehydrogenase as Potential Leads against Mycobacterium tuberculosis.

Author

Park Y, Pacitto A, Bayliss T, Cleghorn LA, Wang Z, Hartman T, Arora K, Ioerger TR, Sacchettini J, Rizzi M, Donini S, Blundell TL, Ascher DB, Rhee K, Breda A, Zhou N, Dartois V, Jonnala SR, Via LE, Mizrahi V, Epemolu O, Stojanovski L, Simeons F, Osuna-Cabello M, Ellis L, MacKenzie CJ, Smith AR, Davis SH, Murugesan D, Buchanan KI, Turner PA, Huggett M, Zuccotto F, Rebollo-Lopez MJ, Lafuente-Monasterio MJ, Sanz O, Diaz GS, Lelièvre J, Ballell L, Selenski C, Axtman M, Ghidelli-Disse S, Pflaumer H, Bösche M, Drewes G, Freiberg GM, Kurnick MD, Srikumaran M, Kempf DJ, Green SR, Ray PC, Read K, Wyatt P, Barry CE 3rd, and Boshoff HI

Subjects
Animals, Drug Design, Drug Discovery, Drug Resistance, Bacterial, Gene Expression Regulation, Bacterial drug effects, Gene Expression Regulation, Enzymologic drug effects, Humans, Mice, Mice, Inbred C57BL, Molecular Structure, Mutation, Protein Conformation, Rabbits, Structure-Activity Relationship, Sulfonamides chemistry, Sulfonamides pharmacokinetics, Tuberculosis drug therapy, Antitubercular Agents pharmacology, IMP Dehydrogenase antagonists & inhibitors, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis enzymology, Sulfonamides pharmacology
Abstract

A potent, noncytotoxic indazole sulfonamide was identified by high-throughput screening of >100,000 synthetic compounds for activity against Mycobacterium tuberculosis (Mtb). This noncytotoxic compound did not directly inhibit cell wall biogenesis but triggered a slow lysis of Mtb cells as measured by release of intracellular green fluorescent protein (GFP). Isolation of resistant mutants followed by whole-genome sequencing showed an unusual gene amplification of a 40 gene region spanning from Rv3371 to Rv3411c and in one case a potential promoter mutation upstream of guaB2 (Rv3411c) encoding inosine monophosphate dehydrogenase (IMPDH). Subsequent biochemical validation confirmed direct inhibition of IMPDH by an uncompetitive mode of inhibition, and growth inhibition could be rescued by supplementation with guanine, a bypass mechanism for the IMPDH pathway. Beads containing immobilized indazole sulfonamides specifically interacted with IMPDH in cell lysates. X-ray crystallography of the IMPDH-IMP-inhibitor complex revealed that the primary interactions of these compounds with IMPDH were direct pi-pi interactions with the IMP substrate. Advanced lead compounds in this series with acceptable pharmacokinetic properties failed to show efficacy in acute or chronic murine models of tuberculosis (TB). Time-kill experiments in vitro suggest that sustained exposure to drug concentrations above the minimum inhibitory concentration (MIC) for 24 h were required for a cidal effect, levels that have been difficult to achieve in vivo. Direct measurement of guanine levels in resected lung tissue from tuberculosis-infected animals and patients revealed 0.5-2 mM concentrations in caseum and normal lung tissue. The high lesional levels of guanine and the slow lytic, growth-rate-dependent effect of IMPDH inhibition pose challenges to developing drugs against this target for use in treating TB.

Published
2017
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