Search

Your search keyword '"Gagaring, Kerstin"' showing total 27 results
Start Over Author "Gagaring, Kerstin"
27 results on '"Gagaring, Kerstin"'

1. Open-source discovery of chemical leads for next-generation chemoprotective antimalarials

Author

Antonova-Koch, Yevgeniya, Meister, Stephan, Abraham, Matthew, Luth, Madeline R, Ottilie, Sabine, Lukens, Amanda K, Sakata-Kato, Tomoyo, Vanaerschot, Manu, Owen, Edward, Jado, Juan Carlos, Maher, Steven P, Calla, Jaeson, Plouffe, David, Zhong, Yang, Chen, Kaisheng, Chaumeau, Victor, Conway, Amy J, McNamara, Case W, Ibanez, Maureen, Gagaring, Kerstin, Serrano, Fernando Neria, Eribez, Korina, Taggard, Cullin McLean, Cheung, Andrea L, Lincoln, Christie, Ambachew, Biniam, Rouillier, Melanie, Siegel, Dionicio, Nosten, François, Kyle, Dennis E, Gamo, Francisco-Javier, Zhou, Yingyao, Llinás, Manuel, Fidock, David A, Wirth, Dyann F, Burrows, Jeremy, Campo, Brice, and Winzeler, Elizabeth A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, HIV/AIDS, Infectious Diseases, Vector-Borne Diseases, Rare Diseases, Malaria, Orphan Drug, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Antimalarials, Chemoprevention, Drug Discovery, Drug Evaluation, Preclinical, Humans, Mitochondria, Plasmodium, General Science & Technology
Abstract

To discover leads for next-generation chemoprotective antimalarial drugs, we tested more than 500,000 compounds for their ability to inhibit liver-stage development of luciferase-expressing Plasmodium spp. parasites (681 compounds showed a half-maximal inhibitory concentration of less than 1 micromolar). Cluster analysis identified potent and previously unreported scaffold families as well as other series previously associated with chemoprophylaxis. Further testing through multiple phenotypic assays that predict stage-specific and multispecies antimalarial activity distinguished compound classes that are likely to provide symptomatic relief by reducing asexual blood-stage parasitemia from those which are likely to only prevent malaria. Target identification by using functional assays, in vitro evolution, or metabolic profiling revealed 58 mitochondrial inhibitors but also many chemotypes possibly with previously unidentified mechanisms of action.

Published
2018

2. Modular, stereocontrolled C β –H/C α –C activation of alkyl carboxylic acids

Author

Shang, Ming, Feu, Karla S., Vantourout, Julien C., Barton, Lisa M., Osswald, Heather L., Kato, Nobutaka, Gagaring, Kerstin, McNamara, Case W., Chen, Gang, Hu, Liang, Ni, Shengyang, Fernández-Canelas, Paula, Chen, Miao, Merchant, Rohan R., Qin, Tian, Schreiber, Stuart L., Melillo, Bruno, Yu, Jin-Quan, and Baran, Phil S.

Published
2019

3. Mutations in the P‑Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials

Author

Flannery, Erika L, McNamara, Case W, Kim, Sang Wan, Kato, Tomoyo Sakata, Li, Fengwu, Teng, Christine H, Gagaring, Kerstin, Manary, Micah J, Barboa, Rachel, Meister, Stephan, Kuhen, Kelli, Vinetz, Joseph M, Chatterjee, Arnab K, and Winzeler, Elizabeth A

Subjects
Biological Sciences, Chemical Sciences, Malaria, Infectious Diseases, Orphan Drug, Rare Diseases, Vector-Borne Diseases, Genetics, Antimicrobial Resistance, Human Genome, Infection, Adenosine Triphosphatases, Antimalarials, Drug Resistance, Gene Expression Regulation, Enzymologic, Indoles, Models, Molecular, Molecular Structure, Mutation, Plasmodium falciparum, Protein Conformation, Pyrazoles, Sodium, Organic Chemistry, Biological sciences, Chemical sciences
Abstract

Aminopyrazoles are a new class of antimalarial compounds identified in a cellular antiparasitic screen with potent activity against Plasmodium falciparum asexual and sexual stage parasites. To investigate their unknown mechanism of action and thus identify their target, we cultured parasites in the presence of a representative member of the aminopyrazole series, GNF-Pf4492, to select for resistance. Whole genome sequencing of three resistant lines showed that each had acquired independent mutations in a P-type cation-transporter ATPase, PfATP4 (PF3D7_1211900), a protein implicated as the novel Plasmodium spp. target of another, structurally unrelated, class of antimalarials called the spiroindolones and characterized as an important sodium transporter of the cell. Similarly to the spiroindolones, GNF-Pf4492 blocks parasite transmission to mosquitoes and disrupts intracellular sodium homeostasis. Our data demonstrate that PfATP4 plays a critical role in cellular processes, can be inhibited by two distinct antimalarial pharmacophores, and supports the recent observations that PfATP4 is a critical antimalarial target.

Published
2015

4. KAF156 Is an Antimalarial Clinical Candidate with Potential for Use in Prophylaxis, Treatment, and Prevention of Disease Transmission

Author

Kuhen, Kelli L, Chatterjee, Arnab K, Rottmann, Matthias, Gagaring, Kerstin, Borboa, Rachel, Buenviaje, Jennifer, Chen, Zhong, Francek, Carolyn, Wu, Tao, Nagle, Advait, Barnes, S Whitney, Plouffe, David, Lee, Marcus CS, Fidock, David A, Graumans, Wouter, van de Vegte-Bolmer, Marga, van Gemert, Geert J, Wirjanata, Grennady, Sebayang, Boni, Marfurt, Jutta, Russell, Bruce, Suwanarusk, Rossarin, Price, Ric N, Nosten, Francois, Tungtaeng, Anchalee, Gettayacamin, Montip, Sattabongkot, Jetsumon, Taylor, Jennifer, Walker, John R, Tully, David, Patra, Kailash P, Flannery, Erika L, Vinetz, Joseph M, Renia, Laurent, Sauerwein, Robert W, Winzeler, Elizabeth A, Glynne, Richard J, and Diagana, Thierry T

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, HIV/AIDS, Orphan Drug, Infectious Diseases, Vector-Borne Diseases, Rare Diseases, Malaria, Prevention, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, Animals, Antimalarials, Imidazoles, Inhibitory Concentration 50, Malaria, Falciparum, Mice, Mice, Inbred ICR, Piperazines, Plasmodium falciparum, Sporozoites, Microbiology, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.

Published
2014

5. KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgi Early Dormant Liver Stage Parasites In Vitro

Author

Zeeman, Anne-Marie, van Amsterdam, Sandra M, McNamara, Case W, der Wel, Annemarie Voorberg-van, Klooster, Els J, van den Berg, Alexander, Remarque, Edmond J, Plouffe, David M, van Gemert, Geert-Jan, Luty, Adrian, Sauerwein, Robert, Gagaring, Kerstin, Borboa, Rachel, Chen, Zhong, Kuhen, Kelli, Glynne, Richard J, Chatterjee, Arnab K, Nagle, Advait, Roland, Jason, Winzeler, Elizabeth A, Leroy, Didier, Campo, Brice, Diagana, Thierry T, Yeung, Bryan KS, Thomas, Alan W, and Kocken, Clemens HM

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Orphan Drug, Digestive Diseases, Liver Disease, Malaria, Prevention, Infectious Diseases, Rare Diseases, Vector-Borne Diseases, Biotechnology, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Good Health and Well Being, Animals, Antimalarials, Drug Evaluation, Preclinical, Female, Hepatocytes, Imidazoles, In Vitro Techniques, Liver, Macaca mulatta, Mice, Mice, Inbred ICR, Plasmodium cynomolgi, Pyrazines, Sporozoites, Microbiology, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Preventing relapses of Plasmodium vivax malaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi (an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgi sporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivax malaria prophylaxis and potentially a radical cure.

Published
2014

6. Targeting Plasmodium PI(4)K to eliminate malaria

Author

McNamara, Case W, Lee, Marcus CS, Lim, Chek Shik, Lim, Siau Hoi, Roland, Jason, Nagle, Advait, Simon, Oliver, Yeung, Bryan KS, Chatterjee, Arnab K, McCormack, Susan L, Manary, Micah J, Zeeman, Anne-Marie, Dechering, Koen J, Kumar, TR Santha, Henrich, Philipp P, Gagaring, Kerstin, Ibanez, Maureen, Kato, Nobutaka, Kuhen, Kelli L, Fischli, Christoph, Rottmann, Matthias, Plouffe, David M, Bursulaya, Badry, Meister, Stephan, Rameh, Lucia, Trappe, Joerg, Haasen, Dorothea, Timmerman, Martijn, Sauerwein, Robert W, Suwanarusk, Rossarin, Russell, Bruce, Renia, Laurent, Nosten, Francois, Tully, David C, Kocken, Clemens HM, Glynne, Richard J, Bodenreider, Christophe, Fidock, David A, Diagana, Thierry T, and Winzeler, Elizabeth A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Orphan Drug, Prevention, Infectious Diseases, Rare Diseases, Malaria, Vector-Borne Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Good Health and Well Being, 1-Phosphatidylinositol 4-Kinase, Adenosine Triphosphate, Animals, Binding Sites, Cytokinesis, Drug Resistance, Fatty Acids, Female, Hepatocytes, Humans, Imidazoles, Life Cycle Stages, Macaca mulatta, Male, Models, Biological, Models, Molecular, Phosphatidylinositol Phosphates, Plasmodium, Pyrazoles, Quinoxalines, Reproducibility of Results, Schizonts, rab GTP-Binding Proteins, General Science & Technology
Abstract

Achieving the goal of malaria elimination will depend on targeting Plasmodium pathways essential across all life stages. Here we identify a lipid kinase, phosphatidylinositol-4-OH kinase (PI(4)K), as the target of imidazopyrazines, a new antimalarial compound class that inhibits the intracellular development of multiple Plasmodium species at each stage of infection in the vertebrate host. Imidazopyrazines demonstrate potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models, are active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax, and inhibit liver-stage hypnozoites in the simian parasite P. cynomolgi. We show that imidazopyrazines exert their effect through inhibitory interaction with the ATP-binding pocket of PI(4)K, altering the intracellular distribution of phosphatidylinositol-4-phosphate. Collectively, our data define PI(4)K as a key Plasmodium vulnerability, opening up new avenues of target-based discovery to identify drugs with an ideal activity profile for the prevention, treatment and elimination of malaria.

Published
2013

7. Imaging of Plasmodium Liver Stages to Drive Next-Generation Antimalarial Drug Discovery

Author

Meister, Stephan, Plouffe, David M., Kuhen, Kelli L., Bonamy, Ghislain M. C., Wu, Tao, Barnes, S. Whitney, Bopp, Selina E., Borboa, Rachel, Bright, A. Taylor, Che, Jianwei, Cohen, Steve, Dharia, Neekesh V., Gagaring, Kerstin, Gettayacamin, Montip, Gordon, Perry, Groessl, Todd, Kato, Nobutaka, Lee, Marcus C. S., McNamara, Case W., Fidock, David A., Nagle, Advait, Nam, Tae-gyu, Richmond, Wendy, Roland, Jason, Rottmann, Matthias, Zhou, Bin, Froissard, Patrick, Glynne, Richard J., Mazier, Dominique, Sattabongkot, Jetsumon, Schultz, Peter G., Tuntland, Tove, Walker, John R., Zhou, Yingyao, Chatterjee, Arnab, Diagana, Thierry T., and Winzeler, Elizabeth A.

Published
2011

9. Probing the Open Global Health Chemical Diversity Library for Multistage-Active Starting Points for Next-Generation Antimalarials

Author

Abraham, Matthew, primary, Gagaring, Kerstin, additional, Martino, Marisa L., additional, Vanaerschot, Manu, additional, Plouffe, David M., additional, Calla, Jaeson, additional, Godinez-Macias, Karla P., additional, Du, Alan Y., additional, Wree, Melanie, additional, Antonova-Koch, Yevgeniya, additional, Eribez, Korina, additional, Luth, Madeline R., additional, Ottilie, Sabine, additional, Fidock, David A., additional, McNamara, Case W., additional, and Winzeler, Elizabeth A., additional

Published
2020
Full Text
View/download PDF

10. Peyssonnosides A–B, unusual diterpene glycosides with a sterically encumbered cyclopropane motif : structure elucidation using an integrated spectroscopic and computational workflow

Author

Khatri Chhetri, Bhuwan, Lavoie, Serge, Sweeney-Jones, Anne Marie, Mojib, Nazia, Raghavan, Vijay, Gagaring, Kerstin, Dale, Brandon, McNamara, Case W., Soapi, Katy, Quave, Cassandra L., Polavarapu, Prasad L., Kubanek, Julia, Khatri Chhetri, Bhuwan, Lavoie, Serge, Sweeney-Jones, Anne Marie, Mojib, Nazia, Raghavan, Vijay, Gagaring, Kerstin, Dale, Brandon, McNamara, Case W., Soapi, Katy, Quave, Cassandra L., Polavarapu, Prasad L., and Kubanek, Julia

Abstract

Two sulfated diterpene glycosides featuring a highly substituted and sterically encumbered cyclopropane ring have been isolated from the marine red alga Peyssonnelia sp. Combination of a wide array of 2D NMR spectroscopic experiments, in a systematic structure elucidation workflow, revealed that peyssonnosides A–B (1–2) represent a new class of diterpene glycosides with a tetracyclo [7.5.0.01,10.05,9] tetradecane architecture. A salient feature of this workflow is the unique application of quantitative interproton distances obtained from the rotating frame Overhauser effect spectroscopy (ROESY) NMR experiment, wherein the β-d-glucose moiety of 1 was used as an internal probe to unequivocally determine the absolute configuration, which was also supported by optical rotatory dispersion (ORD). Peyssonnoside A (1) exhibited promising activity against liver stage Plasmodium berghei and moderate antimethicillin-resistant Staphylococcus aureus (MRSA) activity, with no cytotoxicity against human keratinocytes. Additionally, 1 showed strong growth inhibition of the marine fungus Dendryphiella salina indicating an antifungal ecological role in its natural environment. The high natural abundance and novel carbon skeleton of 1 suggests a rare terpene cyclase machinery, exemplifying the chemical diversity in this phylogenetically distinct marine red alga.

Published
2019

11. Antibacterial oligomeric polyphenols from the green alga Cladophora socialis

Author

Lavoie, Serge, Sweeney-Jones, Anne Marie, Mojib, Nazia, Dale, Brandon, Gagaring, Kerstin, McNamara, Case W., Quave, Cassandra L., Soapi, Katy, Kubanek, Julia, Lavoie, Serge, Sweeney-Jones, Anne Marie, Mojib, Nazia, Dale, Brandon, Gagaring, Kerstin, McNamara, Case W., Quave, Cassandra L., Soapi, Katy, and Kubanek, Julia

Abstract

A series of oligomeric phenols including the known natural product 3,4,3′,4′-tetrahydroxy-1,1′-biphenyl (3), the previously synthesized 2,3,8,9-tetrahydroxybenzo[c]chromen-6-one (4), and eight new related natural products, cladophorols B–I (5–12), were isolated from the Fijian green alga Cladophora socialis and identified by a combination of NMR spectroscopy, mass spectrometric analysis, and computational modeling using DFT calculations. J-resolved spectroscopy and line width reduction by picric acid addition aided in resolving the heavily overlapped aromatic signals. A panel of Gram-positive and Gram-negative pathogens used to evaluate pharmacological potential led to the determination that cladophorol C (6) exhibits potent antibiotic activity selective toward methicillin-resistant Staphylococcus aureus (MRSA) with an MIC of 1.4 μg/mL. Cladophorols B (5) and D–H (7–11) had more modest but also selective antibiotic potency. Activities of cladophorols A–I (4–12) were also assessed against the asexual blood stages of Plasmodium falciparum and revealed cladophorols A (4) and B (5) to have modest activity with EC50 values of 0.7 and 1.9 μg/mL, respectively.

Published
2019

12. Peyssonnosides A–B, Unusual Diterpene Glycosides with a Sterically Encumbered Cyclopropane Motif: Structure Elucidation Using an Integrated Spectroscopic and Computational Workflow

Author

Khatri Chhetri, Bhuwan, primary, Lavoie, Serge, additional, Sweeney-Jones, Anne Marie, additional, Mojib, Nazia, additional, Raghavan, Vijay, additional, Gagaring, Kerstin, additional, Dale, Brandon, additional, McNamara, Case W., additional, Soapi, Katy, additional, Quave, Cassandra L., additional, Polavarapu, Prasad L., additional, and Kubanek, Julia, additional

Published
2019
Full Text
View/download PDF

13. Discovery of short-course antiwolbachial quinazolines for elimination of filarial worm infections

Author

Bakowski, Malina A., primary, Shiroodi, Roohollah Kazem, additional, Liu, Renhe, additional, Olejniczak, Jason, additional, Yang, Baiyuan, additional, Gagaring, Kerstin, additional, Guo, Hui, additional, White, Pamela M., additional, Chappell, Laura, additional, Debec, Alain, additional, Landmann, Frédéric, additional, Dubben, Bettina, additional, Lenz, Franziska, additional, Struever, Dominique, additional, Ehrens, Alexandra, additional, Frohberger, Stefan J., additional, Sjoberg, Hanna, additional, Pionnier, Nicolas, additional, Murphy, Emma, additional, Archer, John, additional, Steven, Andrew, additional, Chunda, Valerine C., additional, Fombad, Fanny F., additional, Chounna, Patrick W., additional, Njouendou, Abdel J., additional, Metuge, Haelly M., additional, Ndzeshang, Bertrand L., additional, Gandjui, Narcisse V., additional, Akumtoh, Desmond N., additional, Kwenti, Tayong D. B., additional, Woods, Ashley K., additional, Joseph, Sean B., additional, Hull, Mitchell V., additional, Xiong, Wen, additional, Kuhen, Kelli L., additional, Taylor, Mark J., additional, Wanji, Samuel, additional, Turner, Joseph D., additional, Hübner, Marc P., additional, Hoerauf, Achim, additional, Chatterjee, Arnab K., additional, Roland, Jason, additional, Tremblay, Matt S., additional, Schultz, Peter G., additional, Sullivan, William, additional, Chu, Xin-Jie, additional, Petrassi, H. Michael, additional, and McNamara, Case W., additional

Published
2019
Full Text
View/download PDF

15. Modular, Stereocontrolled Cβ–H/Cα–C Activation of Alkyl Carboxylic Acids

Author

Shang, Ming, primary, Feu, Karla S., primary, Vantourout, Julien C., primary, Barton, Lisa M., primary, Osswald, HeatherL., primary, Kato, Nobutaka, primary, Gagaring, Kerstin, primary, McNamara, Case W., primary, Chen, Gang, primary, Hu, Liang, primary, Ni, Shengyang, primary, Fernández-Canelas, Paula, primary, Chen, Miao, primary, Merchant, Rohan R., primary, qin, Tian, primary, Schreiber, Stuart, primary, Melillo, Bruno, primary, yu, jin-quan, primary, and Baran, Phil, primary

Published
2019
Full Text
View/download PDF

16. Modular, stereocontrolled Cβ-H/Cα-C activation of alkyl carboxylic acids.

Author

Ming Shang, Feu, Karla S., Vantourout, Julien C., Barton, Lisa M., Osswald, Heather L., Nobutaka Kato, Gagaring, Kerstin, McNamara, Case W., Gang Chen, Liang Hu, Shengyang Ni, Fernández-Canelas, Paula, Miao Chen, Merchant, Rohan R., Tian Qin, Schreiber, Stuart L., Melillo, Bruno, Jin-Quan Yu, and Baran, Phil S.

Subjects
CARBOCYCLIC acids, HETEROCYCLIC compounds, ALKYL compounds, CARBOXYLIC acids, DECARBOXYLATION, DRUG development, ANTIMALARIALS
Abstract

The union of two powerful transformations, directed C-H activation and decarboxylative cross-coupling, for the enantioselective synthesis of vicinally functionalized alkyl, carbocyclic, and heterocyclic compounds is described. Starting from simple carboxylic acid building blocks, this modular sequence exploits the residual directing group to access more than 50 scaffolds that would be otherwise extremely difficult to prepare. The tactical use of these two transformations accomplishes a formal vicinal difunctionalization of carbon centers in a way that is modular and thus, amenable to rapid diversity incorporation. A simplification of routes to known preclinical drug candidates is presented along with the rapid diversification of an antimalarial compound series. [ABSTRACT FROM AUTHOR]

Published
2019
Full Text
View/download PDF

17. High-Throughput Luciferase-Based Assay for the Discovery of Therapeutics That Prevent Malaria

Author

Swann, Justine, primary, Corey, Victoria, additional, Scherer, Christina A., additional, Kato, Nobutaka, additional, Comer, Eamon, additional, Maetani, Micah, additional, Antonova-Koch, Yevgeniya, additional, Reimer, Christin, additional, Gagaring, Kerstin, additional, Ibanez, Maureen, additional, Plouffe, David, additional, Zeeman, Anne-Marie, additional, Kocken, Clemens H. M., additional, McNamara, Case W., additional, Schreiber, Stuart L., additional, Campo, Brice, additional, Winzeler, Elizabeth A., additional, and Meister, Stephan, additional

Published
2016
Full Text
View/download PDF

18. KAF156 is an antimalarial clinical candidate with potential for use in prophylaxis, treatment, and prevention of disease transmission

Author

Kuhen, Kelli L., Chatterjee, Arnab K., Rottmann, Matthias, Gagaring, Kerstin, Borboa, Rachel, Buenviaje, Jennifer, Chen, Zhong, Francek, Carolyn, Wu, Tao, Nagle, Advait, Barnes, S. Whitney, Plouffe, David, Lee, Marcus C.S., Fidock, David A., Graumans, Wouter, van de Vegte-Bolmer, Marga, van Gemert, Geert J., Wirjanata, Grennady, Sebayang, Boni, Marfurt, Jutta, Russell, Bruce, Suwanarusk, Rossarin, Price, Ric N., Nosten, Francois, Tungtaeng, Anchalee, Gettayacamin, Montip, Sattabongkot, Jetsumon, Taylor, Jennifer, Walker, John R., Tully, David, Patra, Kailash P., Flannery, Erika L., Vinetz, Joseph M., Renia, Laurent, Sauerwein, Robert W., Winzeler, Elizabeth A., Glynne, Richard J., Diagana, Thierry T., Kuhen, Kelli L., Chatterjee, Arnab K., Rottmann, Matthias, Gagaring, Kerstin, Borboa, Rachel, Buenviaje, Jennifer, Chen, Zhong, Francek, Carolyn, Wu, Tao, Nagle, Advait, Barnes, S. Whitney, Plouffe, David, Lee, Marcus C.S., Fidock, David A., Graumans, Wouter, van de Vegte-Bolmer, Marga, van Gemert, Geert J., Wirjanata, Grennady, Sebayang, Boni, Marfurt, Jutta, Russell, Bruce, Suwanarusk, Rossarin, Price, Ric N., Nosten, Francois, Tungtaeng, Anchalee, Gettayacamin, Montip, Sattabongkot, Jetsumon, Taylor, Jennifer, Walker, John R., Tully, David, Patra, Kailash P., Flannery, Erika L., Vinetz, Joseph M., Renia, Laurent, Sauerwein, Robert W., Winzeler, Elizabeth A., Glynne, Richard J., and Diagana, Thierry T.

Abstract

Renewed global efforts toward malaria eradication have highlighted the need for novel antimalarial agents with activity against multiple stages of the parasite life cycle. We have previously reported the discovery of a novel class of antimalarial compounds in the imidazolopiperazine series that have activity in the prevention and treatment of blood stage infection in a mouse model of malaria. Consistent with the previously reported activity profile of this series, the clinical candidate KAF156 shows blood schizonticidal activity with 50% inhibitory concentrations of 6 to 17.4 nM against P. falciparum drug-sensitive and drug-resistant strains, as well as potent therapeutic activity in a mouse models of malaria with 50, 90, and 99% effective doses of 0.6, 0.9, and 1.4 mg/kg, respectively. When administered prophylactically in a sporozoite challenge mouse model, KAF156 is completely protective as a single oral dose of 10 mg/kg. Finally, KAF156 displays potent Plasmodium transmission blocking activities both in vitro and in vivo. Collectively, our data suggest that KAF156, currently under evaluation in clinical trials, has the potential to treat, prevent, and block the transmission of malaria.

Published
2014

19. Mutations in the P-Type Cation-Transporter ATPase 4, PfATP4, Mediate Resistance to Both Aminopyrazole and Spiroindolone Antimalarials

Author

Flannery, Erika L., primary, McNamara, Case W., additional, Kim, Sang Wan, additional, Kato, Tomoyo Sakata, additional, Li, Fengwu, additional, Teng, Christine H., additional, Gagaring, Kerstin, additional, Manary, Micah J., additional, Barboa, Rachel, additional, Meister, Stephan, additional, Kuhen, Kelli, additional, Vinetz, Joseph M., additional, Chatterjee, Arnab K., additional, and Winzeler, Elizabeth A., additional

Published
2014
Full Text
View/download PDF

20. Lead Optimization of Imidazopyrazines: A New Class of Antimalarial with Activity on Plasmodium Liver Stages

Author

Zou, Bin, primary, Nagle, Advait, additional, Chatterjee, Arnab K., additional, Leong, Seh Yong, additional, Tan, Liying Jocelyn, additional, Sim, Wei Lin Sandra, additional, Mishra, Pranab, additional, Guntapalli, Prasuna, additional, Tully, David C., additional, Lakshminarayana, Suresh B., additional, Lim, Chek Shik, additional, Tan, Yong Cheng, additional, Abas, Siti Nurdiana, additional, Bodenreider, Christophe, additional, Kuhen, Kelli L., additional, Gagaring, Kerstin, additional, Borboa, Rachel, additional, Chang, Jonathan, additional, Li, Chun, additional, Hollenbeck, Thomas, additional, Tuntland, Tove, additional, Zeeman, Anne-Marie, additional, Kocken, Clemens H. M., additional, McNamara, Case, additional, Kato, Nobutaka, additional, Winzeler, Elizabeth A., additional, Yeung, Bryan K. S., additional, Diagana, Thierry T., additional, Smith, Paul W., additional, and Roland, Jason, additional

Published
2014
Full Text
View/download PDF

21. KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgi Early Dormant Liver Stage ParasitesIn Vitro

Author

Zeeman, Anne-Marie, primary, van Amsterdam, Sandra M., additional, McNamara, Case W., additional, Voorberg-van der Wel, Annemarie, additional, Klooster, Els J., additional, van den Berg, Alexander, additional, Remarque, Edmond J., additional, Plouffe, David M., additional, van Gemert, Geert-Jan, additional, Luty, Adrian, additional, Sauerwein, Robert, additional, Gagaring, Kerstin, additional, Borboa, Rachel, additional, Chen, Zhong, additional, Kuhen, Kelli, additional, Glynne, Richard J., additional, Chatterjee, Arnab K., additional, Nagle, Advait, additional, Roland, Jason, additional, Winzeler, Elizabeth A., additional, Leroy, Didier, additional, Campo, Brice, additional, Diagana, Thierry T., additional, Yeung, Bryan K. S., additional, Thomas, Alan W., additional, and Kocken, Clemens H. M., additional

Published
2014
Full Text
View/download PDF

22. Indolcarboxamide Is a Preclinical Candidate for Treating Multidrug-Resistant Tuberculosis

Author

Rao, Srinivasa P. S., primary, Lakshminarayana, Suresh B., additional, Kondreddi, Ravinder R., additional, Herve, Maxime, additional, Camacho, Luis R., additional, Bifani, Pablo, additional, Kalapala, Sarath K., additional, Jiricek, Jan, additional, Ma, Ng L., additional, Tan, Bee H., additional, Ng, Seow H., additional, Nanjundappa, Mahesh, additional, Ravindran, Sindhu, additional, Seah, Peck G., additional, Thayalan, Pamela, additional, Lim, Siao H., additional, Lee, Boon H., additional, Goh, Anne, additional, Barnes, Whitney S., additional, Chen, Zhong, additional, Gagaring, Kerstin, additional, Chatterjee, Arnab K., additional, Pethe, Kevin, additional, Kuhen, Kelli, additional, Walker, John, additional, Feng, Gu, additional, Babu, Sreehari, additional, Zhang, Lijun, additional, Blasco, Francesca, additional, Beer, David, additional, Weaver, Margaret, additional, Dartois, Veronique, additional, Glynne, Richard, additional, Dick, Thomas, additional, Smith, Paul W., additional, Diagana, Thierry T., additional, and Manjunatha, Ujjini H., additional

Published
2013
Full Text
View/download PDF

23. Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents

Author

Nagle, Advait, primary, Wu, Tao, additional, Kuhen, Kelli, additional, Gagaring, Kerstin, additional, Borboa, Rachel, additional, Francek, Caroline, additional, Chen, Zhong, additional, Plouffe, David, additional, Lin, Xuena, additional, Caldwell, Christopher, additional, Ek, Jared, additional, Skolnik, Suzanne, additional, Liu, Fenghua, additional, Wang, Jianling, additional, Chang, Jonathan, additional, Li, Chun, additional, Liu, Bo, additional, Hollenbeck, Thomas, additional, Tuntland, Tove, additional, Isbell, John, additional, Chuan, Tiffany, additional, Alper, Philip B., additional, Fischli, Christoph, additional, Brun, Reto, additional, Lakshminarayana, Suresh B., additional, Rottmann, Matthias, additional, Diagana, Thierry T., additional, Winzeler, Elizabeth A., additional, Glynne, Richard, additional, Tully, David C., additional, and Chatterjee, Arnab K., additional

Published
2012
Full Text
View/download PDF

24. Imidazolopiperazines: Hit to Lead Optimization of New Antimalarial Agents

Author

Wu, Tao, primary, Nagle, Advait, additional, Kuhen, Kelli, additional, Gagaring, Kerstin, additional, Borboa, Rachel, additional, Francek, Caroline, additional, Chen, Zhong, additional, Plouffe, David, additional, Goh, Anne, additional, Lakshminarayana, Suresh B., additional, Wu, Jeanette, additional, Ang, Hui Qing, additional, Zeng, Peiting, additional, Kang, Min Low, additional, Tan, William, additional, Tan, Maria, additional, Ye, Nicole, additional, Lin, Xuena, additional, Caldwell, Christopher, additional, Ek, Jared, additional, Skolnik, Suzanne, additional, Liu, Fenghua, additional, Wang, Jianling, additional, Chang, Jonathan, additional, Li, Chun, additional, Hollenbeck, Thomas, additional, Tuntland, Tove, additional, Isbell, John, additional, Fischli, Christoph, additional, Brun, Reto, additional, Rottmann, Matthias, additional, Dartois, Veronique, additional, Keller, Thomas, additional, Diagana, Thierry, additional, Winzeler, Elizabeth, additional, Glynne, Richard, additional, Tully, David C., additional, and Chatterjee, Arnab K., additional

Published
2011
Full Text
View/download PDF

25. Identification of inhibitors for putative malaria drug targets among novel antimalarial compounds

Author

Crowther, Gregory J., primary, Napuli, Alberto J., additional, Gilligan, James H., additional, Gagaring, Kerstin, additional, Borboa, Rachel, additional, Francek, Carolyn, additional, Chen, Zhong, additional, Dagostino, Eleanor F., additional, Stockmyer, Justin B., additional, Wang, Yu, additional, Rodenbough, Philip P., additional, Castaneda, Lisa J., additional, Leibly, David J., additional, Bhandari, Janhavi, additional, Gelb, Michael H., additional, Brinker, Achim, additional, Engels, Ingo H., additional, Taylor, Jennifer, additional, Chatterjee, Arnab K., additional, Fantauzzi, Pascal, additional, Glynne, Richard J., additional, Van Voorhis, Wesley C., additional, and Kuhen, Kelli L., additional

Published
2011
Full Text
View/download PDF

26. KAI407, a Potent Non-8-Aminoquinoline Compound That Kills Plasmodium cynomolgiEarly Dormant Liver Stage Parasites In Vitro

Author

Zeeman, Anne-Marie, van Amsterdam, Sandra M., McNamara, Case W., Voorberg-van der Wel, Annemarie, Klooster, Els J., van den Berg, Alexander, Remarque, Edmond J., Plouffe, David M., van Gemert, Geert-Jan, Luty, Adrian, Sauerwein, Robert, Gagaring, Kerstin, Borboa, Rachel, Chen, Zhong, Kuhen, Kelli, Glynne, Richard J., Chatterjee, Arnab K., Nagle, Advait, Roland, Jason, Winzeler, Elizabeth A., Leroy, Didier, Campo, Brice, Diagana, Thierry T., Yeung, Bryan K. S., Thomas, Alan W., and Kocken, Clemens H. M.

Abstract

ABSTRACTPreventing relapses of Plasmodium vivaxmalaria through a radical cure depends on use of the 8-aminoquinoline primaquine, which is associated with safety and compliance issues. For future malaria eradication strategies, new, safer radical curative compounds that efficiently kill dormant liver stages (hypnozoites) will be essential. A new compound with potential radical cure activity was identified using a low-throughput assay of in vitro-cultured hypnozoite forms of Plasmodium cynomolgi(an excellent and accessible model for Plasmodium vivax). In this assay, primary rhesus hepatocytes are infected with P. cynomolgisporozoites, and exoerythrocytic development is monitored in the presence of compounds. Liver stage cultures are fixed after 6 days and stained with anti-Hsp70 antibodies, and the relative proportions of small (hypnozoite) and large (schizont) forms relative to the untreated controls are determined. This assay was used to screen a series of 18 known antimalarials and 14 new non-8-aminoquinolines (preselected for blood and/or liver stage activity) in three-point 10-fold dilutions (0.1, 1, and 10 μM final concentrations). A novel compound, designated KAI407 showed an activity profile similar to that of primaquine (PQ), efficiently killing the earliest stages of the parasites that become either primary hepatic schizonts or hypnozoites (50% inhibitory concentration [IC50] for hypnozoites, KAI407, 0.69 μM, and PQ, 0.84 μM; for developing liver stages, KAI407, 0.64 μM, and PQ, 0.37 μM). When given as causal prophylaxis, a single oral dose of 100 mg/kg of body weight prevented blood stage parasitemia in mice. From these results, we conclude that KAI407 may represent a new compound class for P. vivaxmalaria prophylaxis and potentially a radical cure.

Published
2014
Full Text
View/download PDF

27. Antimalarial Peptide and Polyketide Natural Products from the Fijian Marine Cyanobacterium Moorea producens

Author

Mojib, Nazia, Spelman College (Author), Sweeney-Jones, Anne Marie, Georgia Institute of Technology (Author), Gagaring, Kerstin, Calibr, a division of The Scripps Research Institute (Author), Antonova-Koch, Jenya, Calibr, a division of The Scripps Research Institute (Author), Zhou, Hongyi, Georgia Institute of Technology (Author), Soapi,Katy, University of the South Pacific (Author), Skolnick, Jeffrey, Georgia Institute of Technology (Author), McNamara, Case W., Calibr, a division of The Scripps Research Institute (Author), Kubanek, Julia, Georgia Institute of Technology (Author), Mojib, Nazia, Spelman College (Author), Sweeney-Jones, Anne Marie, Georgia Institute of Technology (Author), Gagaring, Kerstin, Calibr, a division of The Scripps Research Institute (Author), Antonova-Koch, Jenya, Calibr, a division of The Scripps Research Institute (Author), Zhou, Hongyi, Georgia Institute of Technology (Author), Soapi,Katy, University of the South Pacific (Author), Skolnick, Jeffrey, Georgia Institute of Technology (Author), McNamara, Case W., Calibr, a division of The Scripps Research Institute (Author), and Kubanek, Julia, Georgia Institute of Technology (Author)

Abstract

A new cyclic peptide, kakeromamide B (1), and previously described cytotoxic cyanobacterial natural products ulongamide A (2), lyngbyabellin A (3), 18E-lyngbyaloside C (4), and lyngbyaloside (5) were identified from an antimalarial extract of the Fijian marine cyanobacterium Moorea producens. Compounds 1 and 2 exhibited moderate activity against Plasmodium falciparum blood-stages with EC50 values of 0.89 and 0.99 M, respectively, whereas 3 was more potent with an EC50 value of 0.15 nM. Compounds 1, 4, and 5 displayed moderate liver-stage antimalarial activity against P. berghei liver schizonts with EC50 values of 1.1, 0.71, and 0.45 M, respectively. The threading-based computational method FINDSITEcomb2.0 predicted the binding of 1 and 2 to potentially druggable proteins of Plasmodium falciparum, prompting formulation of hypotheses about possible mechanisms of action. Kakeromamide B (1) was predicted to bind to several Plasmodium actin-like proteins and a sortilin protein suggesting possible interference with parasite invasion of host cells. When 1 was tested in a mammalian actin polymerization assay, it stimulated actin polymerization in a dose-dependent manner, suggesting that 1 does, in fact, interact with actin.

Catalog

Books, media, physical & digital resources
See catalog results