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242 results on '"Angulo-Barturen, Iñigo"'

1. Identification of potent and reversible piperidine carboxamides that are species-selective orally active proteasome inhibitors to treat malaria

Author

Lawong, Aloysus, Gahalawat, Suraksha, Ray, Sneha, Ho, Nhi, Han, Yan, Ward, Kurt E., Deng, Xiaoyi, Chen, Zhe, Kumar, Ashwani, Xing, Chao, Hosangadi, Varun, Fairhurst, Kate J., Tashiro, Kyuto, Liszczak, Glen, Shackleford, David M., Katneni, Kasiram, Chen, Gong, Saunders, Jessica, Crighton, Elly, Casas, Arturo, Robinson, Joshua J., Imlay, Leah S., Zhang, Xiaoyu, Lemoff, Andrew, Zhao, Zhiyu, Angulo-Barturen, Iñigo, Jiménez-Díaz, María Belén, Wittlin, Sergio, Campbell, Simon F., Fidock, David A., Laleu, Benoît, Charman, Susan A., Ready, Joseph M., and Phillips, Margaret A.

Published
2024
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2. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Author

de Vries, Laura E., Jansen, Patrick A. M., Barcelo, Catalina, Munro, Justin, Verhoef, Julie M. J., Pasaje, Charisse Flerida A., Rubiano, Kelly, Striepen, Josefine, Abla, Nada, Berning, Luuk, Bolscher, Judith M., Demarta-Gatsi, Claudia, Henderson, Rob W. M., Huijs, Tonnie, Koolen, Karin M. J., Tumwebaze, Patrick K., Yeo, Tomas, Aguiar, Anna C. C., Angulo-Barturen, Iñigo, Churchyard, Alisje, Baum, Jake, Fernández, Benigno Crespo, Fuchs, Aline, Gamo, Francisco-Javier, Guido, Rafael V. C., Jiménez-Diaz, María Belén, Pereira, Dhelio B., Rochford, Rosemary, Roesch, Camille, Sanz, Laura M., Trevitt, Graham, Witkowski, Benoit, Wittlin, Sergio, Cooper, Roland A., Rosenthal, Philip J., Sauerwein, Robert W., Schalkwijk, Joost, Hermkens, Pedro H. H., Bonnert, Roger V., Campo, Brice, Fidock, David A., Llinás, Manuel, Niles, Jacquin C., Kooij, Taco W. A., and Dechering, Koen J.

Published
2022
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3. 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

4. A novel multiple-stage antimalarial agent that inhibits protein synthesis

Author

Baragaña, Beatriz, Hallyburton, Irene, Lee, Marcus CS, 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, 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, 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
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Biotechnology, Infectious Diseases, Malaria, Orphan Drug, Vector-Borne Diseases, Rare Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Animals, Antimalarials, Drug Discovery, Female, Gene Expression Regulation, Life Cycle Stages, Liver, Male, Models, Molecular, Peptide Elongation Factor 2, Plasmodium, Plasmodium berghei, Plasmodium falciparum, Plasmodium vivax, Protein Biosynthesis, Quinolines, General Science & Technology
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.

Published
2015

5. (+)-SJ733, a clinical candidate for malaria that acts through ATP4 to induce rapid host-mediated clearance of Plasmodium

Author

Jiménez-Díaz, María Belén, Ebert, Daniel, Salinas, Yandira, Pradhan, Anupam, Lehane, Adele M, Myrand-Lapierre, Marie-Eve, O’Loughlin, Kathleen G, Shackleford, David M, de Almeida, Mariana Justino, Carrillo, Angela K, Clark, Julie A, Dennis, Adelaide SM, Diep, Jonathon, Deng, Xiaoyan, Duffy, Sandra, Endsley, Aaron N, Fedewa, Greg, Guiguemde, W Armand, Gómez, María G, Holbrook, Gloria, Horst, Jeremy, Kim, Charles C, Liu, Jian, Lee, Marcus CS, Matheny, Amy, Martínez, María Santos, Miller, Gregory, Rodríguez-Alejandre, Ane, Sanz, Laura, Sigal, Martina, Spillman, Natalie J, Stein, Philip D, Wang, Zheng, Zhu, Fangyi, Waterson, David, Knapp, Spencer, Shelat, Anang, Avery, Vicky M, Fidock, David A, Gamo, Francisco-Javier, Charman, Susan A, Mirsalis, Jon C, Ma, Hongshen, Ferrer, Santiago, Kirk, Kiaran, Angulo-Barturen, Iñigo, Kyle, Dennis E, DeRisi, Joseph L, Floyd, David M, and Guy, R Kiplin

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Vector-Borne Diseases, Antimicrobial Resistance, Malaria, Infectious Diseases, Orphan Drug, Rare Diseases, 2.2 Factors relating to the physical environment, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Aetiology, 2.1 Biological and endogenous factors, Infection, Good Health and Well Being, Antimalarials, Calcium-Transporting ATPases, Cellular Senescence, Drug Discovery, Drug Resistance, Erythrocytes, Flow Cytometry, Heterocyclic Compounds, 4 or More Rings, High-Throughput Screening Assays, Isoquinolines, Models, Molecular, Molecular Structure, Plasmodium, malaria, PfATP4, drug discovery
Abstract

Drug discovery for malaria has been transformed in the last 5 years by the discovery of many new lead compounds identified by phenotypic screening. The process of developing these compounds as drug leads and studying the cellular responses they induce is revealing new targets that regulate key processes in the Plasmodium parasites that cause malaria. We disclose herein that the clinical candidate (+)-SJ733 acts upon one of these targets, ATP4. ATP4 is thought to be a cation-transporting ATPase responsible for maintaining low intracellular Na(+) levels in the parasite. Treatment of parasitized erythrocytes with (+)-SJ733 in vitro caused a rapid perturbation of Na(+) homeostasis in the parasite. This perturbation was followed by profound physical changes in the infected cells, including increased membrane rigidity and externalization of phosphatidylserine, consistent with eryptosis (erythrocyte suicide) or senescence. These changes are proposed to underpin the rapid (+)-SJ733-induced clearance of parasites seen in vivo. Plasmodium falciparum ATPase 4 (pfatp4) mutations that confer resistance to (+)-SJ733 carry a high fitness cost. The speed with which (+)-SJ733 kills parasites and the high fitness cost associated with resistance-conferring mutations appear to slow and suppress the selection of highly drug-resistant mutants in vivo. Together, our data suggest that inhibitors of PfATP4 have highly attractive features for fast-acting antimalarials to be used in the global eradication campaign.

Published
2014

7. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitro and In Vivo Antimalarial Activity

Author

Kovada, Vadims, primary, Withers-Martinez, Chrislaine, additional, Bobrovs, Raitis, additional, Ce̅rule, Hele̅na, additional, Liepins, Edgars, additional, Grinberga, Solveiga, additional, Hackett, Fiona, additional, Collins, Christine R., additional, Kreicberga, Agrita, additional, Jiménez-Díaz, María Belén, additional, Angulo-Barturen, Iñigo, additional, Rasina, Dace, additional, Suna, Edgars, additional, Jaudzems, Kristaps, additional, Blackman, Michael J., additional, and Jirgensons, Aigars, additional

Published
2023
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8. Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

Author

O' Neill, Paul M., Stocks, Paul A., Sabbani, Sunil, Roberts, Natalie L., Amewu, Richard K., Shore, Emma R., Aljayyoussi, Ghaith, Angulo-Barturén, Iñigo, Belén, María, Jiménez-Díaz, Bazaga, Santiago Ferrer, Martínez, María Santos, Campo, Brice, Sharma, Raman, Charman, Susan A., Ryan, Eileen, Chen, Gong, Shackleford, David M., Davies, Jill, Nixon, Gemma L., Biagini, Giancarlo A., and Ward, Stephen A.

Published
2018
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9. A new in vivo screening paradigm to accelerate antimalarial drug discovery.

Author

Jiménez-Díaz, María, Viera, Sara, Ibáñez, Javier, Mulet, Teresa, Magán-Marchal, Noemí, Garuti, Helen, Gómez, Vanessa, Cortés-Gil, Lorena, Martínez, Antonio, Ferrer, Santiago, Fraile, María, Calderón, Félix, Fernández, Esther, Shultz, Leonard, Leroy, Didier, García-Bustos, José, Gamo, Francisco, Angulo-Barturen, Iñigo, and Wilson, David

Subjects
Animals, Antimalarials, Drug Evaluation, Preclinical, Feasibility Studies, Female, Humans, Malaria, Mice, Parasitemia, Plasmodium berghei, Time Factors
Abstract

The emergence of resistance to available antimalarials requires the urgent development of new medicines. The recent disclosure of several thousand compounds active in vitro against the erythrocyte stage of Plasmodium falciparum has been a major breakthrough, though converting these hits into new medicines challenges current strategies. A new in vivo screening concept was evaluated as a strategy to increase the speed and efficiency of drug discovery projects in malaria. The new in vivo screening concept was developed based on human disease parameters, i.e. parasitemia in the peripheral blood of patients on hospital admission and parasite reduction ratio (PRR), which were allometrically down-scaled into P. berghei-infected mice. Mice with an initial parasitemia (P0) of 1.5% were treated orally for two consecutive days and parasitemia measured 24 h after the second dose. The assay was optimized for detection of compounds able to stop parasite replication (PRR = 1) or induce parasite clearance (PRR >1) with statistical power >99% using only two mice per experimental group. In the P. berghei in vivo screening assay, the PRR of a set of eleven antimalarials with different mechanisms of action correlated with human-equivalent data. Subsequently, 590 compounds from the Tres Cantos Antimalarial Set with activity in vitro against P. falciparum were tested at 50 mg/kg (orally) in an assay format that allowed the evaluation of hundreds of compounds per month. The rate of compounds with detectable efficacy was 11.2% and about one third of active compounds showed in vivo efficacy comparable with the most potent antimalarials used clinically. High-throughput, high-content in vivo screening could rapidly select new compounds, dramatically speeding up the discovery of new antimalarial medicines. A global multilateral collaborative project aimed at screening the significant chemical diversity within the antimalarial in vitro hits described in the literature is a feasible task.

Published
2013

10. Chemical genetics of Plasmodium falciparum

Author

Guiguemde, W Armand, Shelat, Anang A, Bouck, David, Duffy, Sandra, Crowther, Gregory J, Davis, Paul H, Smithson, David C, Connelly, Michele, Clark, Julie, Zhu, Fangyi, Jiménez-Díaz, María B, Martinez, María S, Wilson, Emily B, Tripathi, Abhai K, Gut, Jiri, Sharlow, Elizabeth R, Bathurst, Ian, Mazouni, Farah El, Fowble, Joseph W, Forquer, Isaac, McGinley, Paula L, Castro, Steve, Angulo-Barturen, Iñigo, Ferrer, Santiago, Rosenthal, Philip J, DeRisi, Joseph L, Sullivan, David J, Lazo, John S, Roos, David S, Riscoe, Michael K, Phillips, Margaret A, Rathod, Pradipsinh K, Van Voorhis, Wesley C, Avery, Vicky M, and Guy, R Kiplin

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Genetics, Antimicrobial Resistance, Orphan Drug, Vector-Borne Diseases, Malaria, Emerging Infectious Diseases, Biotechnology, Rare Diseases, Biodefense, Infectious Diseases, 2.2 Factors relating to the physical environment, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Animals, Antimalarials, Cell Line, Drug Discovery, Drug Evaluation, Preclinical, Drug Resistance, Drug Therapy, Combination, Erythrocytes, Humans, Malaria, Falciparum, Mice, Phenotype, Phylogeny, Plasmodium falciparum, Reproducibility of Results, Small Molecule Libraries, General Science & Technology
Abstract

Malaria caused by Plasmodium falciparum is a disease that is responsible for 880,000 deaths per year worldwide. Vaccine development has proved difficult and resistance has emerged for most antimalarial drugs. To discover new antimalarial chemotypes, we have used a phenotypic forward chemical genetic approach to assay 309,474 chemicals. Here we disclose structures and biological activity of the entire library-many of which showed potent in vitro activity against drug-resistant P. falciparum strains-and detailed profiling of 172 representative candidates. A reverse chemical genetic study identified 19 new inhibitors of 4 validated drug targets and 15 novel binders among 61 malarial proteins. Phylochemogenetic profiling in several organisms revealed similarities between Toxoplasma gondii and mammalian cell lines and dissimilarities between P. falciparum and related protozoans. One exemplar compound displayed efficacy in a murine model. Our findings provide the scientific community with new starting points for malaria drug discovery.

Published
2010

11. Predicting Optimal Antimalarial Drug Combinations from a Standardized Plasmodium falciparum Humanized Mouse Model

Author

Demarta-Gatsi, Claudia, primary, Andenmatten, Nicole, additional, Jiménez-Díaz, María-Belén, additional, Gobeau, Nathalie, additional, Cherkaoui-Rabti, Mohammed H., additional, Fuchs, Aline, additional, Díaz, Pablo, additional, Berja, Sandra, additional, Sánchez, Rebeca, additional, Gómez, Hazel, additional, Ruiz, Estíbaliz, additional, Sainz, Paula, additional, Salazar, Eider, additional, Gil-Merino, Rodrigo, additional, Mendoza, Luis Manuel, additional, Eguizabal, Cristina, additional, Leroy, Didier, additional, Moehrle, Joerg J., additional, Tornesi, Belen, additional, and Angulo-Barturen, Iñigo, additional

Published
2023
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12. A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes.

Author

Angulo-Barturen, Iñigo, Jiménez-Díaz, María Belén, Mulet, Teresa, Rullas, Joaquín, Herreros, Esperanza, Ferrer, Santiago, Jiménez, Elena, Mendoza, Alfonso, Regadera, Javier, Rosenthal, Philip J, Bathurst, Ian, Pompliano, David L, Gómez de las Heras, Federico, and Gargallo-Viola, Domingo

Subjects
Animals, Mice, Inbred NOD, Humans, Mice, Plasmodium falciparum, Malaria, Falciparum, Erythrocyte Transfusion, Transplantation, Heterologous, Inbred NOD, Malaria, Falciparum, Transplantation, Heterologous, General Science & Technology
Abstract

To counter the global threat caused by Plasmodium falciparum malaria, new drugs and vaccines are urgently needed. However, there are no practical animal models because P. falciparum infects human erythrocytes almost exclusively. Here we describe a reliable falciparum murine model of malaria by generating strains of P. falciparum in vivo that can infect immunodeficient mice engrafted with human erythrocytes. We infected NOD(scid/beta2m-/-) mice engrafted with human erythrocytes with P. falciparum obtained from in vitro cultures. After apparent clearance, we obtained isolates of P. falciparum able to grow in peripheral blood of engrafted NOD(scid/beta2m-/-) mice. Of the isolates obtained, we expanded in vivo and established the isolate Pf3D7(0087/N9) as a reference strain for model development. Pf3D7(0087/N9) caused productive persistent infections in 100% of engrafted mice infected intravenously. The infection caused a relative anemia due to selective elimination of human erythrocytes by a mechanism dependent on parasite density in peripheral blood. Using this model, we implemented and validated a reproducible assay of antimalarial activity useful for drug discovery. Thus, our results demonstrate that P. falciparum contains clones able to grow reproducibly in mice engrafted with human erythrocytes without the use of myeloablative methods.

Published
2008

14. Discovery and Characterization of Potent, Efficacious, Orally Available Antimalarial Plasmepsin X Inhibitors and Preclinical Safety Assessment of UCB7362

Author

Lowe, Martin A., primary, Cardenas, Alvaro, additional, Valentin, Jean-Pierre, additional, Zhu, Zhaoning, additional, Abendroth, Jan, additional, Castro, Jose L., additional, Class, Reiner, additional, Delaunois, Annie, additional, Fleurance, Renaud, additional, Gerets, Helga, additional, Gryshkova, Vitalina, additional, King, Lloyd, additional, Lorimer, Donald D., additional, MacCoss, Malcolm, additional, Rowley, Julian H., additional, Rosseels, Marie-Luce, additional, Royer, Leandro, additional, Taylor, Richard D., additional, Wong, Melanie, additional, Zaccheo, Oliver, additional, Chavan, Vishal P., additional, Ghule, Gokul A., additional, Tapkir, Bapusaheb K., additional, Burrows, Jeremy N., additional, Duffey, Maëlle, additional, Rottmann, Matthias, additional, Wittlin, Sergio, additional, Angulo-Barturen, Iñigo, additional, Jiménez-Díaz, María Belén, additional, Striepen, Josefine, additional, Fairhurst, Kate J., additional, Yeo, Tomas, additional, Fidock, David A., additional, Cowman, Alan F., additional, Favuzza, Paola, additional, Crespo-Fernandez, Benigno, additional, Gamo, Francisco Javier, additional, Goldberg, Daniel E., additional, Soldati-Favre, Dominique, additional, Laleu, Benoît, additional, and de Haro, Teresa, additional

Published
2022
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17. A Plasmodium berghei sporozoite-based vaccination platform against human malaria

Author

Mendes, António M., Machado, Marta, Gonçalves-Rosa, Nataniel, Reuling, Isaie J., Foquet, Lander, Marques, Cláudia, Salman, Ahmed M., Yang, Annie S. P., Moser, Kara A., Dwivedi, Ankit, Hermsen, Cornelus C., Jiménez-Díaz, Belén, Viera, Sara, Santos, Jorge M., Albuquerque, Inês, Bhatia, Sangeeta N., Bial, John, Angulo-Barturen, Iñigo, Silva, Joana C., Leroux-Roels, Geert, Janse, Chris J., Khan, Shahid M., Mota, Maria M., Sauerwein, Robert W., and Prudêncio, Miguel

Published
2018
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18. Macrocyclic Peptidomimetic Plasmepsin X Inhibitors with Potent In Vitroand In VivoAntimalarial Activity

Author

Kovada, Vadims, Withers-Martinez, Chrislaine, Bobrovs, Raitis, Ce̅rule, Hele̅na, Liepins, Edgars, Grinberga, Solveiga, Hackett, Fiona, Collins, Christine R., Kreicberga, Agrita, Jiménez-Díaz, María Belén, Angulo-Barturen, Iñigo, Rasina, Dace, Suna, Edgars, Jaudzems, Kristaps, Blackman, Michael J., and Jirgensons, Aigars

Abstract

The Plasmodium falciparumaspartic protease plasmepsin X (PMX) is essential for the egress of invasive merozoite forms of the parasite. PMX has therefore emerged as a new potential antimalarial target. Building on peptidic amino alcohols originating from a phenotypic screening hit, we have here developed a series of macrocyclic analogues as PMX inhibitors. Incorporation of an extended linker between the S1 phenyl group and S3 amide led to a lead compound that displayed a 10-fold improved PMX inhibitory potency and a 3-fold improved half-life in microsomal stability assays compared to the acyclic analogue. The lead compound was also the most potent of the new macrocyclic compounds in in vitroparasite growth inhibition. Inhibitor 7kcleared blood-stage P. falciparumin a dose-dependent manner when administered orally to infected humanized mice. Consequently, lead compound 7krepresents a promising orally bioavailable molecule for further development as a PMX-targeting antimalarial drug.

Published
2023
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20. Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria

Author

Taft, Benjamin R., primary, Yokokawa, Fumiaki, additional, Kirrane, Tom, additional, Mata, Anne-Catherine, additional, Huang, Richard, additional, Blaquiere, Nicole, additional, Waldron, Grace, additional, Zou, Bin, additional, Simon, Oliver, additional, Vankadara, Subramanyam, additional, Chan, Wai Ling, additional, Ding, Mei, additional, Sim, Sandra, additional, Straimer, Judith, additional, Guiguemde, Armand, additional, Lakshminarayana, Suresh B., additional, Jain, Jay Prakash, additional, Bodenreider, Christophe, additional, Thompson, Christopher, additional, Lanshoeft, Christian, additional, Shu, Wei, additional, Fang, Eric, additional, Qumber, Jafri, additional, Chan, Katherine, additional, Pei, Luying, additional, Chen, Yen-Liang, additional, Schulz, Hanna, additional, Lim, Jessie, additional, Abas, Siti Nurdiana, additional, Ang, Xiaoman, additional, Liu, Yugang, additional, Angulo-Barturen, Iñigo, additional, Jiménez-Díaz, María Belén, additional, Gamo, Francisco Javier, additional, Crespo-Fernandez, Benigno, additional, Rosenthal, Philip J., additional, Cooper, Roland A., additional, Tumwebaze, Patrick, additional, Aguiar, Anna Caroline Campos, additional, Campo, Brice, additional, Campbell, Simon, additional, Wagner, Jürgen, additional, Diagana, Thierry T., additional, and Sarko, Christopher, additional

Published
2022
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21. Study of Tissue-Specific Reactive Oxygen Species Formation by Cell Membrane Microarrays for the Characterization of Bioactive Compounds

Author

Elexpe, Ane, primary, Nieto, Nerea, additional, Fernández-Cuétara, Claudia, additional, Domínguez-Fernández, Celtia, additional, Morera-Herreras, Teresa, additional, Torrecilla, María, additional, Miguélez, Cristina, additional, Laso, Antonio, additional, Ochoa, Eneko, additional, Bailen, María, additional, González-Coloma, Azucena, additional, Angulo-Barturen, Iñigo, additional, Astigarraga, Egoitz, additional, and Barreda-Gómez, Gabriel, additional

Published
2021
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22. Enzyme Therapy: Current Challenges and Future Perspectives

Author

de la Fuente, Miguel, primary, Lombardero, Laura, additional, Gómez-González, Alfonso, additional, Solari, Cristina, additional, Angulo-Barturen, Iñigo, additional, Acera, Arantxa, additional, Vecino, Elena, additional, Astigarraga, Egoitz, additional, and Barreda-Gómez, Gabriel, additional

Published
2021
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23. The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance

Author

Murithi, James M., primary, Pascal, Cécile, additional, Bath, Jade, additional, Boulenc, Xavier, additional, Gnädig, Nina F., additional, Pasaje, Charisse Flerida A., additional, Rubiano, Kelly, additional, Yeo, Tomas, additional, Mok, Sachel, additional, Klieber, Sylvie, additional, Desert, Paul, additional, Jiménez-Díaz, María Belén, additional, Marfurt, Jutta, additional, Rouillier, Mélanie, additional, Cherkaoui-Rbati, Mohammed H., additional, Gobeau, Nathalie, additional, Wittlin, Sergio, additional, Uhlemann, Anne-Catrin, additional, Price, Ric N., additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Tumwebaze, Patrick, additional, Cooper, Roland A., additional, Rosenthal, Philip J., additional, Sanz, Laura M., additional, Gamo, Francisco Javier, additional, Joseph, Jayan, additional, Singh, Shivendra, additional, Bashyam, Sridevi, additional, Augereau, Jean Michel, additional, Giraud, Elie, additional, Bozec, Tanguy, additional, Vermat, Thierry, additional, Tuffal, Gilles, additional, Guillon, Jean-Michel, additional, Menegotto, Jérôme, additional, Sallé, Laurent, additional, Louit, Guillaume, additional, Cabanis, Marie-José, additional, Nicolas, Marie Françoise, additional, Doubovetzky, Michel, additional, Merino, Rita, additional, Bessila, Nadir, additional, Angulo-Barturen, Iñigo, additional, Baud, Delphine, additional, Bebrevska, Lidiya, additional, Escudié, Fanny, additional, Niles, Jacquin C., additional, Blasco, Benjamin, additional, Campbell, Simon, additional, Courtemanche, Gilles, additional, Fraisse, Laurent, additional, Pellet, Alain, additional, Fidock, David A., additional, and Leroy, Didier, additional

Published
2021
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24. Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Author

de Vries, Laura E., primary, Jansen, Patrick A.M., additional, Barcelo, Catalina, additional, Munro, Justin, additional, Verhoef, Julie M.J., additional, Pasaje, Charisse Flerida A., additional, Rubiano, Kelly, additional, Striepen, Josefine, additional, Bolscher, Judith M., additional, Henderson, Rob, additional, Huijs, Tonnie, additional, Koolen, Karin M.J., additional, Tumwebaze, Patrick K., additional, Yeo, Tomas, additional, Aguiar, Anna C.C., additional, Angulo-Barturen, Iñigo, additional, Churchyard, Alisje, additional, Baum, Jake, additional, Fernández, Benigno Crespo, additional, Gamo, Francisco-Javier, additional, Guido, Rafael V.C., additional, Jiménez-Diaz, María Belén, additional, Pereira, Dhelio B., additional, Rochford, Rosemary, additional, Sanz, Laura M., additional, Trevitt, Graham, additional, Wittlin, Sergio, additional, Cooper, Roland A., additional, Rosenthal, Philip J., additional, Sauerwein, Robert W., additional, Schalkwijk, Joost, additional, Hermkens, Pedro H.H., additional, Bonnert, Roger, additional, Campo, Brice, additional, Fidock, David A., additional, Llinás, Manuel, additional, Niles, Jacquin C., additional, Kooij, Taco W.A., additional, and Dechering, Koen J., additional

Published
2021
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25. Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series

Author

Palmer, Michael J., primary, Deng, Xiaoyi, additional, Watts, Shawn, additional, Krilov, Goran, additional, Gerasyuto, Aleksey, additional, Kokkonda, Sreekanth, additional, El Mazouni, Farah, additional, White, John, additional, White, Karen L., additional, Striepen, Josefine, additional, Bath, Jade, additional, Schindler, Kyra A., additional, Yeo, Tomas, additional, Shackleford, David M., additional, Mok, Sachel, additional, Deni, Ioanna, additional, Lawong, Aloysus, additional, Huang, Ann, additional, Chen, Gong, additional, Wang, Wen, additional, Jayaseelan, Jaya, additional, Katneni, Kasiram, additional, Patil, Rahul, additional, Saunders, Jessica, additional, Shahi, Shatrughan P., additional, Chittimalla, Rajesh, additional, Angulo-Barturen, Iñigo, additional, Jiménez-Díaz, María Belén, additional, Wittlin, Sergio, additional, Tumwebaze, Patrick K., additional, Rosenthal, Philip J., additional, Cooper, Roland A., additional, Aguiar, Anna Caroline Campos, additional, Guido, Rafael V. C., additional, Pereira, Dhelio B., additional, Mittal, Nimisha, additional, Winzeler, Elizabeth A., additional, Tomchick, Diana R., additional, Laleu, Benoît, additional, Burrows, Jeremy N., additional, Rathod, Pradipsinh K., additional, Fidock, David A., additional, Charman, Susan A., additional, and Phillips, Margaret A., additional

Published
2021
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26. Chemoprotective Antimalarial Activity of P218 against Plasmodium falciparum: A Randomized, Placebo-Controlled Volunteer Infection Study

Author

Chughlay, Mohamed Farouk, primary, El Gaaloul, Myriam, additional, Donini, Cristina, additional, Campo, Brice, additional, Berghmans, Pieter-Jan, additional, Lucardie, Alexander, additional, Marx, Michael W., additional, Cherkaoui-Rbati, Mohammed H., additional, Langdon, Grant, additional, Angulo-Barturen, Iñigo, additional, Viera, Sara, additional, Rosanas-Urgell, Anna, additional, Van Geertruyden, Jean-Pierre, additional, and Chalon, Stephan, additional

Published
2021
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29. Characterization of Novel Antimalarial Compound ACT-451840: Preclinical Assessment of Activity and Dose-Efficacy Modeling

Author

Le Bihan, Amélie, de Kanter, Ruben, Angulo-Barturen, Iñigo, Binkert, Christoph, Boss, Christoph, Brun, Reto, Brunner, Ralf, Buchmann, Stephan, Burrows, Jeremy, Dechering, Koen J., Delves, Michael, Ewerling, Sonja, Ferrer, Santiago, Fischli, Christoph, Gamo-Benito, Francisco Javier, Gnädig, Nina F., Heidmann, Bibia, Jiménez-Díaz, María Belén, Leroy, Didier, Martínez, Maria Santos, Meyer, Solange, Moehrle, Joerg J., Ng, Caroline L., Noviyanti, Rintis, Ruecker, Andrea, Sanz, Laura María, Sauerwein, Robert W., Scheurer, Christian, Schleiferboeck, Sarah, Sinden, Robert, Snyder, Christopher, Straimer, Judith, Wirjanata, Grennady, Marfurt, Jutta, Price, Ric N., Weller, Thomas, Fischli, Walter, Fidock, David A., Clozel, Martine, and Wittlin, Sergio

Subjects
Antimalarials -- Models -- Usage -- Analysis -- Dosage and administration -- Complications and side effects, Plasmodium falciparum -- Models -- Analysis -- Physiological aspects -- Research, Malaria -- Analysis -- Models -- Drug therapy -- Research, Biological sciences
Abstract

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3-4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11-16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23-39). The compound's preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (C.sub.max ), and time above a threshold concentration. The determination of the dose-efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study., Author(s): Amélie Le Bihan 1, Ruben de Kanter 1, Iñigo Angulo-Barturen 2, Christoph Binkert 1, Christoph Boss 1, Reto Brun 3,4, Ralf Brunner 1,3,4, Stephan Buchmann 1, Jeremy Burrows 5, [...]

Published
2016
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30. A novel class of fast‐acting antimalarial agents: Substituted 15‐membered azalides

Author

Peric, Mihaela, primary, Pešić, Dijana, additional, Alihodžić, Sulejman, additional, Fajdetić, Andrea, additional, Herreros, Esperanza, additional, Gamo, Francisco Javier, additional, Angulo‐Barturen, Iñigo, additional, Jiménez‐Díaz, María Belén, additional, Ferrer‐Bazaga, Santiago, additional, Martínez, María S., additional, Gargallo‐Viola, Domingo, additional, Mathis, Amanda, additional, Kessler, Albane, additional, Banjanac, Mihailo, additional, Padovan, Jasna, additional, Bencetić Mihaljević, Vlatka, additional, Munic Kos, Vesna, additional, Bukvić, Mirjana, additional, Eraković Haber, Vesna, additional, and Spaventi, Radan, additional

Published
2020
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32. 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

33. Optimized Pyridazinone Nutrient Channel Inhibitors Are Potent and Specific Antimalarial Leads

Author

Butler, Michelle M., Waidyarachchi, Samanthi L., Shao, Jinfeng, Nguyen, Son T., Ding, Xiaoyuan, Cardinale, Steven C., Morin, Lucas R., Kwasny, Steven M., Ito, Mai, Gezelle, Jeanine, Jiménez-Díaz, María B., Angulo-Barturen, Iñigo, Jacobs, Robert T., Burrows, Jeremy N., Aron, Zachary D., Bowlin, Terry L., and Desai, Sanjay A.

Abstract

Human and animal malaria parasites increase their host erythrocyte permeability to a broad range of solutes as mediated by parasite-associated ion channels. Molecular and pharmacological studies have implicated an essential role in parasite nutrient acquisition, but inhibitors suitable for development of antimalarial drugs are missing. Here, we generated a potent and specific drug lead using Plasmodium falciparum, a virulent human pathogen, and derivatives of MBX-2366, a nanomolar affinity pyridazinone inhibitor from a high-throughput screen. As this screening hit lacks the bioavailability and stability needed for in vivo efficacy, we synthesized 315 derivatives to optimize drug-like properties, establish target specificity, and retain potent activity against the parasite-induced permeability. Using a robust, iterative pipeline, we generated MBX-4055, a derivative active against divergent human parasite strains. MBX-4055 has improved oral absorption with acceptable in vivo tolerability and pharmacokinetics. It also has no activity against a battery of 35 human channels and receptors and is refractory to acquired resistance during extended in vitro selection. Single-molecule and single-cell patch-clamp indicate direct action on the plasmodial surface anion channel, a channel linked to parasite-encoded RhopH proteins. These studies identify pyridazinones as novel and tractable antimalarial scaffolds with a defined mechanism of action.SIGNIFICANCE STATEMENTBecause antimalarial drugs are prone to evolving resistance in the virulent human P. falciparumpathogen, new therapies are needed. This study has now developed a novel drug-like series of pyridazinones that target an unexploited parasite anion channel on the host cell surface, display excellent in vitro and in vivo ADME properties, are refractory to acquired resistance, and demonstrate a well defined mechanism of action.

Published
2022
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34. Antimalarial pantothenamide metabolites target acetyl–coenzyme A biosynthesis in Plasmodium falciparum

Author

Schalkwijk, Joost, primary, Allman, Erik L., additional, Jansen, Patrick A. M., additional, de Vries, Laura E., additional, Verhoef, Julie M. J., additional, Jackowski, Suzanne, additional, Botman, Peter N. M., additional, Beuckens-Schortinghuis, Christien A., additional, Koolen, Karin M. J., additional, Bolscher, Judith M., additional, Vos, Martijn W., additional, Miller, Karen, additional, Reeves, Stacy A., additional, Pett, Helmi, additional, Trevitt, Graham, additional, Wittlin, Sergio, additional, Scheurer, Christian, additional, Sax, Sibylle, additional, Fischli, Christoph, additional, Angulo-Barturen, Iñigo, additional, Jiménez-Diaz, Mariá Belén, additional, Josling, Gabrielle, additional, Kooij, Taco W. A., additional, Bonnert, Roger, additional, Campo, Brice, additional, Blaauw, Richard H., additional, Rutjes, Floris P. J. T., additional, Sauerwein, Robert W., additional, Llinás, Manuel, additional, Hermkens, Pedro H. H., additional, and Dechering, Koen J., additional

Published
2019
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35. Erratum for Brunschwig et al., “UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria”

Author

Brunschwig, Christel, primary, Lawrence, Nina, additional, Taylor, Dale, additional, Abay, Efrem, additional, Njoroge, Mathew, additional, Basarab, Gregory S., additional, Le Manach, Claire, additional, Paquet, Tanya, additional, Gonzàlez Cabrera, Diego, additional, Nchinda, Aloysius T., additional, de Kock, Carmen, additional, Wiesner, Lubbe, additional, Denti, Paolo, additional, Waterson, David, additional, Blasco, Benjamin, additional, Leroy, Didier, additional, Witty, Michael J., additional, Donini, Cristina, additional, Duffy, James, additional, Wittlin, Sergio, additional, White, Karen L., additional, Charman, Susan A., additional, Jiménez-Díaz, Maria Belén, additional, Angulo-Barturen, Iñigo, additional, Herreros, Esperanza, additional, Gamo, Francisco Javier, additional, Rochford, Rosemary, additional, Mancama, Dalu, additional, Coetzer, Theresa L., additional, van der Watt, Mariëtte E., additional, Reader, Janette, additional, Birkholtz, Lyn-Marie, additional, Marsh, Kennan C., additional, Solapure, Suresh M., additional, Burke, John E., additional, McPhail, Jacob A., additional, Vanaerschot, Manu, additional, Fidock, David A., additional, Fish, Paul V., additional, Siegl, Peter, additional, Smith, Dennis A., additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, Silue, Kigbafori D., additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2018
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36. A novel class of fast-acting antimalarial agents: Substituted 15-membered azalides.

Author

Peric, Mihaela, Pešić, Dijana, Alihodžić, Sulejman, Fajdetić, Andrea, Herreros, Esperanza, Gamo, Francisco Javier, Angulo‐Barturen, Iñigo, Jiménez‐Díaz, María Belén, Ferrer‐Bazaga, Santiago, Martínez, María S., Gargallo‐Viola, Domingo, Mathis, Amanda, Kessler, Albane, Banjanac, Mihailo, Padovan, Jasna, Bencetić Mihaljević, Vlatka, Munic Kos, Vesna, Bukvić, Mirjana, Eraković Haber, Vesna, and Spaventi, Radan

Subjects
ANTIMALARIALS, ERYTHROCYTES, BIOAVAILABILITY, BLOOD cells, BLOOD parasites, DRUG resistance, AZITHROMYCIN, ARTEMISININ derivatives, DRUG therapy for malaria, PROTOZOA, RESEARCH, ANIMAL experimentation, RESEARCH methodology, MEDICAL cooperation, EVALUATION research, RATS, COMPARATIVE studies, RESEARCH funding, CHLOROQUINE, DOGS, MICE, PHARMACODYNAMICS
Abstract

Background and Purpose: Efficacy of current antimalarial treatments is declining as a result of increasing antimalarial drug resistance, so new and potent antimalarial drugs are urgently needed. Azithromycin, an azalide antibiotic, was found useful in malaria therapy, but its efficacy in humans is low.Experimental Approach: Four compounds belonging to structurally different azalide classes were tested and their activities compared to azithromycin and chloroquine. in vitro evaluation included testing against sensitive and resistant Plasmodium falciparum, cytotoxicity against HepG2 cells, accumulation and retention in human erythrocytes, antibacterial activity, and mode of action studies (delayed death phenotype and haem polymerization). in vivo assessment enabled determination of pharmacokinetic profiles in mice, rats, dogs, and monkeys and in vivo efficacy in a humanized mouse model.Key Results: Novel fast-acting azalides were highly active in vitro against P. falciparum strains exhibiting various resistance patterns, including chloroquine-resistant strains. Excellent antimalarial activity was confirmed in a P. falciparum murine model by strong inhibition of haemozoin-containing trophozoites and quick clearance of parasites from the blood. Pharmacokinetic analysis revealed that compounds are metabolically stable and have moderate oral bioavailability, long half-lives, low clearance, and substantial exposures, with blood cells as the preferred compartment, especially infected erythrocytes. Fast anti-plasmodial action is achieved by the high accumulation into infected erythrocytes and interference with parasite haem polymerization, a mode of action different from slow-acting azithromycin.Conclusion and Implications: The hybrid derivatives described here represent excellent antimalarial drug candidates with the potential for clinical use in malaria therapy. [ABSTRACT FROM AUTHOR]

Published
2021
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37. UCT943, a Next-Generation Plasmodium falciparum PI4K Inhibitor Preclinical Candidate for the Treatment of Malaria

Author

Brunschwig, Christel, primary, Lawrence, Nina, additional, Taylor, Dale, additional, Abay, Efrem, additional, Njoroge, Mathew, additional, Basarab, Gregory S., additional, Le Manach, Claire, additional, Paquet, Tanya, additional, Cabrera, Diego Gonzàlez, additional, Nchinda, Aloysius T., additional, de Kock, Carmen, additional, Wiesner, Lubbe, additional, Denti, Paolo, additional, Waterson, David, additional, Blasco, Benjamin, additional, Leroy, Didier, additional, Witty, Michael J., additional, Donini, Cristina, additional, Duffy, James, additional, Wittlin, Sergio, additional, White, Karen L., additional, Charman, Susan A., additional, Jiménez-Díaz, Maria Belén, additional, Angulo-Barturen, Iñigo, additional, Herreros, Esperanza, additional, Gamo, Francisco Javier, additional, Rochford, Rosemary, additional, Mancama, Dalu, additional, Coetzer, Theresa L., additional, van der Watt, Mariëtte E., additional, Reader, Janette, additional, Birkholtz, Lyn-Marie, additional, Marsh, Kennan C., additional, Solapure, Suresh M., additional, Burke, John E., additional, McPhail, Jacob A., additional, Vanaerschot, Manu, additional, Fidock, David A., additional, Fish, Paul V., additional, Siegl, Peter, additional, Smith, Dennis A., additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, Silue, Kigbafori D., additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2018
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38. Identification of Fast-Acting 2,6-Disubstituted Imidazopyridines That Are Efficacious in the in Vivo Humanized Plasmodium falciparum NODscidIL2Rγnull Mouse Model of Malaria

Author

Nchinda, Aloysius T., primary, Le Manach, Claire, additional, Paquet, Tanya, additional, Gonzàlez Cabrera, Diego, additional, Wicht, Kathryn J., additional, Brunschwig, Christel, additional, Njoroge, Mathew, additional, Abay, Efrem, additional, Taylor, Dale, additional, Lawrence, Nina, additional, Wittlin, Sergio, additional, Jiménez-Díaz, María-Belén, additional, Santos Martínez, María, additional, Ferrer, Santiago, additional, Angulo-Barturen, Iñigo, additional, Lafuente-Monasterio, Maria Jose, additional, Duffy, James, additional, Burrows, Jeremy, additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2018
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39. Synthesis and Structure–Activity Relationships of the Novel Antimalarials 5-Pyridinyl-4(1H)-Pyridones

Author

Bueno, José M., primary, Calderon, Félix, additional, Chicharro, Jesús, additional, De la Rosa, Juan C., additional, Díaz, Beatriz, additional, Fernández, Jorge, additional, Fiandor, José M., additional, Fraile, María T., additional, García, Mercedes, additional, Herreros, Esperanza, additional, García-Pérez, Adolfo, additional, Lorenzo, Milagros, additional, Mallo, Araceli, additional, Puente, Margarita, additional, Saadeddin, Anas, additional, Ferrer, Santiago, additional, Angulo-Barturen, Iñigo, additional, Burrows, Jeremy N., additional, and León, María L., additional

Published
2018
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40. Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

Author

Martínez-Hoyos, María, Perez-Herran, Esther, Gulten, Gulcin, Encinas, Lourdes, Álvarez-Gómez, Daniel, Alvarez, Emilio, Ferrer-Bazaga, Santiago, García-Pérez, Adolfo, Ortega, Fátima, Angulo-Barturen, Iñigo, Rullas-Trincado, Joaquin, Blanco Ruano, Delia, Torres, Pedro, Castañeda, Pablo, Huss, Sophie, Fernández Menéndez, Raquel, González del Valle, Silvia, Ballell, Lluis, Barros, David, Modha, Sundip, Dhar, Neeraj, Signorino-Gelo, François, McKinney, John D., García-Bustos, Jose Francisco, Lavandera, Jose Luis, Sacchettini, James C., Jimenez, M. Soledad, Martín-Casabona, Nuria, Castro-Pichel, Julia, Mendoza-Losana, Alfonso, Universitat Autònoma de Barcelona, GlaxoSmithKline, and Unión Europea. Comisión Europea. 7 Programa Marco

Subjects
0301 basic medicine, Models, Molecular, Protein Conformation, Antibiotics, Antitubercular Agents, lcsh:Medicine, Pharmacology, Reductase, Mice, Catalytic Domain, Tuberculosis, Multidrug-Resistant, Enzyme Inhibitors, Animal Enoyl, media_common, lcsh:R5-920, biology, INHA, Drug discovery, Isoniazid, General Medicine, Catalase, Enoyl-(Acyl-Carrier-Protein) Reductase (NADH), 3. Good health, Female, lcsh:Medicine (General), Research Paper, medicine.drug, Protein Binding, Drug, Tuberculosis, medicine.drug_class, media_common.quotation_subject, 030106 microbiology, Microbial Sensitivity Tests, General Biochemistry, Genetics and Molecular Biology, Mycobacterium tuberculosis, 03 medical and health sciences, Medicine, General & Internal, InhA, Microsomes, medicine, Animals, Humans, Biology, Binding Sites, lcsh:R, Antibiotic, Single-cell imaging, biology.organism_classification, medicine.disease, bacterial infections and mycoses, Disease Models, Animal, 030104 developmental biology, Mutation, Bactericidal, Rifampicin
Abstract

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment., Highlights • KatG-independent InhA inhibitors mimicking isoniazid cidality • GSK693 first DI showing oral in vivo efficacy similar to isoniazid • Retain activity against M(X)DR clinical isolates • Physicochemical properties akin to antitubercular drugs Last year, Mycobacterium tuberculosis had the doubtful honor of being the top infectious killer worldwide. The current 6-month treatment, which was developed more than 30 years ago, has saved million of lives but bears the drawback of poor compliance; hence, the world needs a new shorter and safer TB treatment. The biochemical screening of GSK compound library performed by Martinez et al. has identified new KatG-independent inhibitor of InhA active against M(X)DR Mtb strains, good drug-like properties, and in vivo activity similar to isoniazid overcoming the resistance and toxicological issues of the former drug.

Published
2016

41. Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

Author

Norcross, Neil R., Baragaña, Beatriz, Wilson, Caroline, Hallyburton, Irene, Osuna-Cabello, Maria, Norval, Suzanne, Riley, Jennifer, Stojanovski, Laste, Simeons, Frederick R. C., Porzelle, Achim, Grimaldi, Raffaella, Wittlin, Sergio, Duffy, Sandra, Avery, Vicky M., Meister, Stephan, Sanz, Laura, Jiménez-Díaz, Belén, Angulo-Barturen, Iñigo, Ferrer, Santiago, Martínez, María Santos, Gamo, Francisco Javier, Frearson, Julie A., Gray, David W., Fairlamb, Alan H., Winzeler, Elizabeth A., Waterson, David, Campbell, Simon F., Willis, Paul, Read, Kevin D., and Gilbert, Ian H.

Subjects
Antimalarials, Pyrimidines, Plasmodium berghei, parasitic diseases, Plasmodium falciparum, Animals, Humans, Mice, SCID, Malaria, Falciparum, Parasitemia, Article, Malaria
Abstract

In this paper we describe the optimization of a phenotypic hit against Plasmodium falciparum, based on a trisubstituted pyrimidine scaffold. This led to compounds with good pharmacokinetics and oral activity in a P. berghei mouse model of malaria. The most promising compound (13) showed a reduction in parasitemia of 96% when dosed at 30 mg/kg orally once a day for 4 days in the P. berghei mouse model of malaria. It also demonstrated a rapid rate of clearance of the erythrocytic stage of P. falciparum in the SCID mouse model with an ED90 of 11.7 mg/kg when dosed orally. Unfortunately, the compound is a potent inhibitor of cytochrome P450 enzymes, probably due to a 4-pyridyl substituent. Nevertheless, this is a lead molecule with a potentially useful antimalarial profile, which could either be further optimized or be used for target hunting.

Published
2016

42. Discovery of a Potent and Specific M. tuberculosis Leucyl-tRNA Synthetase Inhibitor: (S)-3-(Aminomethyl)-4-chloro-7-(2-hydroxyethoxy)benzo[c][1,2]oxaborol-1(3H)-ol (GSK656)

Author

Li, Xianfeng, primary, Hernandez, Vincent, additional, Rock, Fernando L., additional, Choi, Wai, additional, Mak, Yvonne S. L., additional, Mohan, Manisha, additional, Mao, Weimin, additional, Zhou, Yasheen, additional, Easom, Eric E., additional, Plattner, Jacob J., additional, Zou, Wuxin, additional, Pérez-Herrán, Esther, additional, Giordano, Ilaria, additional, Mendoza-Losana, Alfonso, additional, Alemparte, Carlos, additional, Rullas, Joaquín, additional, Angulo-Barturen, Iñigo, additional, Crouch, Sabrinia, additional, Ortega, Fátima, additional, Barros, David, additional, and Alley, M. R. K., additional

Published
2017
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43. Antimalarial efficacy of MMV390048, an inhibitor of Plasmodium phosphatidylinositol 4-kinase

Author

Paquet, Tanya, primary, Le Manach, Claire, additional, Cabrera, Diego González, additional, Younis, Yassir, additional, Henrich, Philipp P., additional, Abraham, Tara S., additional, Lee, Marcus C. S., additional, Basak, Rajshekhar, additional, Ghidelli-Disse, Sonja, additional, Lafuente-Monasterio, María José, additional, Bantscheff, Marcus, additional, Ruecker, Andrea, additional, Blagborough, Andrew M., additional, Zakutansky, Sara E., additional, Zeeman, Anne-Marie, additional, White, Karen L., additional, Shackleford, David M., additional, Mannila, Janne, additional, Morizzi, Julia, additional, Scheurer, Christian, additional, Angulo-Barturen, Iñigo, additional, Martínez, María Santos, additional, Ferrer, Santiago, additional, Sanz, Laura María, additional, Gamo, Francisco Javier, additional, Reader, Janette, additional, Botha, Mariette, additional, Dechering, Koen J., additional, Sauerwein, Robert W., additional, Tungtaeng, Anchalee, additional, Vanachayangkul, Pattaraporn, additional, Lim, Chek Shik, additional, Burrows, Jeremy, additional, Witty, Michael J., additional, Marsh, Kennan C., additional, Bodenreider, Christophe, additional, Rochford, Rosemary, additional, Solapure, Suresh M., additional, Jiménez-Díaz, María Belén, additional, Wittlin, Sergio, additional, Charman, Susan A., additional, Donini, Cristina, additional, Campo, Brice, additional, Birkholtz, Lyn-Marie, additional, Hanson, Kirsten K., additional, Drewes, Gerard, additional, Kocken, Clemens H. M., additional, Delves, Michael J., additional, Leroy, Didier, additional, Fidock, David A., additional, Waterson, David, additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2017
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44. Identification of a Potential Antimalarial Drug Candidate from a Series of 2-Aminopyrazines by Optimization of Aqueous Solubility and Potency across the Parasite Life Cycle

Author

Le Manach, Claire, primary, Nchinda, Aloysius T., additional, Paquet, Tanya, additional, Gonzàlez Cabrera, Diego, additional, Younis, Yassir, additional, Han, Ze, additional, Bashyam, Sridevi, additional, Zabiulla, Mohammed, additional, Taylor, Dale, additional, Lawrence, Nina, additional, White, Karen L., additional, Charman, Susan A., additional, Waterson, David, additional, Witty, Michael J., additional, Wittlin, Sergio, additional, Botha, Mariëtte E., additional, Nondaba, Sindisiswe H., additional, Reader, Janette, additional, Birkholtz, Lyn-Marie, additional, Jiménez-Díaz, María Belén, additional, Martínez, María Santos, additional, Ferrer, Santiago, additional, Angulo-Barturen, Iñigo, additional, Meister, Stephan, additional, Antonova-Koch, Yevgeniya, additional, Winzeler, Elizabeth A., additional, Street, Leslie J., additional, and Chibale, Kelly, additional

Published
2016
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45. A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria

Author

Phillips, Margaret A., primary, White, Karen L., additional, Kokkonda, Sreekanth, additional, Deng, Xiaoyi, additional, White, John, additional, El Mazouni, Farah, additional, Marsh, Kennan, additional, Tomchick, Diana R., additional, Manjalanagara, Krishne, additional, Rudra, Kakali Rani, additional, Wirjanata, Grennady, additional, Noviyanti, Rintis, additional, Price, Ric N., additional, Marfurt, Jutta, additional, Shackleford, David M., additional, Chiu, Francis C. K., additional, Campbell, Michael, additional, Jimenez-Diaz, Maria Belen, additional, Bazaga, Santiago Ferrer, additional, Angulo-Barturen, Iñigo, additional, Martinez, Maria Santos, additional, Lafuente-Monasterio, Maria, additional, Kaminsky, Werner, additional, Silue, Kigbafori, additional, Zeeman, Anne-Marie, additional, Kocken, Clemens, additional, Leroy, Didier, additional, Blasco, Benjamin, additional, Rossignol, Emilie, additional, Rueckle, Thomas, additional, Matthews, Dave, additional, Burrows, Jeremy N., additional, Waterson, David, additional, Palmer, Michael J., additional, Rathod, Pradipsinh K., additional, and Charman, Susan A., additional

Published
2016
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46. Discovery of Novel Oral Protein Synthesis Inhibitors of Mycobacterium tuberculosis That Target Leucyl-tRNA Synthetase

Author

Palencia, Andrés, primary, Li, Xianfeng, additional, Bu, Wei, additional, Choi, Wai, additional, Ding, Charles Z., additional, Easom, Eric E., additional, Feng, Lisa, additional, Hernandez, Vincent, additional, Houston, Paul, additional, Liu, Liang, additional, Meewan, Maliwan, additional, Mohan, Manisha, additional, Rock, Fernando L., additional, Sexton, Holly, additional, Zhang, Suoming, additional, Zhou, Yasheen, additional, Wan, Baojie, additional, Wang, Yuehong, additional, Franzblau, Scott G., additional, Woolhiser, Lisa, additional, Gruppo, Veronica, additional, Lenaerts, Anne J., additional, O'Malley, Theresa, additional, Parish, Tanya, additional, Cooper, Christopher B., additional, Waters, M. Gerard, additional, Ma, Zhenkun, additional, Ioerger, Thomas R., additional, Sacchettini, James C., additional, Rullas, Joaquín, additional, Angulo-Barturen, Iñigo, additional, Pérez-Herrán, Esther, additional, Mendoza, Alfonso, additional, Barros, David, additional, Cusack, Stephen, additional, Plattner, Jacob J., additional, and Alley, M. R. K., additional

Published
2016
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47. Identification of KasA as the cellular target of an anti-tubercular scaffold

Author

Abrahams, Katherine A., primary, Chung, Chun-wa, additional, Ghidelli-Disse, Sonja, additional, Rullas, Joaquín, additional, Rebollo-López, María José, additional, Gurcha, Sudagar S., additional, Cox, Jonathan A. G., additional, Mendoza, Alfonso, additional, Jiménez-Navarro, Elena, additional, Martínez-Martínez, María Santos, additional, Neu, Margarete, additional, Shillings, Anthony, additional, Homes, Paul, additional, Argyrou, Argyrides, additional, Casanueva, Ruth, additional, Loman, Nicholas J., additional, Moynihan, Patrick J., additional, Lelièvre, Joël, additional, Selenski, Carolyn, additional, Axtman, Matthew, additional, Kremer, Laurent, additional, Bantscheff, Marcus, additional, Angulo-Barturen, Iñigo, additional, Izquierdo, Mónica Cacho, additional, Cammack, Nicholas C., additional, Drewes, Gerard, additional, Ballell, Lluis, additional, Barros, David, additional, Besra, Gurdyal S., additional, and Bates, Robert H., additional

Published
2016
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48. Trisubstituted Pyrimidines as Efficacious and Fast-Acting Antimalarials

Author

Norcross, Neil R., primary, Baragaña, Beatriz, additional, Wilson, Caroline, additional, Hallyburton, Irene, additional, Osuna-Cabello, Maria, additional, Norval, Suzanne, additional, Riley, Jennifer, additional, Stojanovski, Laste, additional, Simeons, Frederick R. C., additional, Porzelle, Achim, additional, Grimaldi, Raffaella, additional, Wittlin, Sergio, additional, Duffy, Sandra, additional, Avery, Vicky M., additional, Meister, Stephan, additional, Sanz, Laura, additional, Jiménez-Díaz, Belén, additional, Angulo-Barturen, Iñigo, additional, Ferrer, Santiago, additional, Martínez, María Santos, additional, Gamo, Francisco Javier, additional, Frearson, Julie A., additional, Gray, David W., additional, Fairlamb, Alan H., additional, Winzeler, Elizabeth A., additional, Waterson, David, additional, Campbell, Simon F., additional, Willis, Paul, additional, Read, Kevin D., additional, and Gilbert, Ian H., additional

Published
2016
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49. Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

Author

Martínez-Hoyos, María, primary, Perez-Herran, Esther, additional, Gulten, Gulcin, additional, Encinas, Lourdes, additional, Álvarez-Gómez, Daniel, additional, Alvarez, Emilio, additional, Ferrer-Bazaga, Santiago, additional, García-Pérez, Adolfo, additional, Ortega, Fátima, additional, Angulo-Barturen, Iñigo, additional, Rullas-Trincado, Joaquin, additional, Blanco Ruano, Delia, additional, Torres, Pedro, additional, Castañeda, Pablo, additional, Huss, Sophie, additional, Fernández Menéndez, Raquel, additional, González del Valle, Silvia, additional, Ballell, Lluis, additional, Barros, David, additional, Modha, Sundip, additional, Dhar, Neeraj, additional, Signorino-Gelo, François, additional, McKinney, John D., additional, García-Bustos, Jose Francisco, additional, Lavandera, Jose Luis, additional, Sacchettini, James C., additional, Jimenez, M. Soledad, additional, Martín-Casabona, Nuria, additional, Castro-Pichel, Julia, additional, and Mendoza-Losana, Alfonso, additional

Published
2016
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50. Linking Murine and Human Plasmodium falciparum Challenge Models in a Translational Path for Antimalarial Drug Development

Author

McCarthy, James S., primary, Marquart, Louise, additional, Sekuloski, Silvana, additional, Trenholme, Katharine, additional, Elliott, Suzanne, additional, Griffin, Paul, additional, Rockett, Rebecca, additional, O'Rourke, Peter, additional, Sloots, Theo, additional, Angulo-Barturen, Iñigo, additional, Ferrer, Santiago, additional, Jiménez-Díaz, María Belén, additional, Martínez, María-Santos, additional, van Huijsduijnen, Rob Hooft, additional, Duparc, Stephan, additional, Leroy, Didier, additional, Wells, Timothy N. C., additional, Baker, Mark, additional, and Möhrle, Jörg J., additional

Published
2016
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