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Full-Text Articles in Medicine and Health Sciences
Preclinical Characterization And Target Validation Of The Antimalarial Pantothenamide Mmv693183., Laura E. De Vries, Patrick A. M. Jansen, Catalina Barcelo, Justin Munro, Julie M. J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W. M. Henderson, Tonnie Huijs, Karin M J Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C. C. Aguiar, Iñigo Angulo-Barturen, Alisje Churchyard, Jake Baum, Benigno Crespo Fernández, Aline Fuchs, Francisco-Javier Gamo, Rafael V. C. Guido, María Belén Jiménez-Diaz, Dhelio B. Pereira, Rosemary Rochford, Camille Roesch, Laura M. Sanz, Graham Trevitt, Benoit Witkowski, Sergio Wittlin, Roland A. Cooper, Philip J. Rosenthal, Robert W. Sauerwein, Joost Schalkwijk, Pedro H. H. Hermkens, Roger V. Bonnert, Brice Campo, David A. Fidock, Manuel Llinás, Jacquin C. Niles, Taco W. A. Kooij, Koen J. Dechering
Preclinical Characterization And Target Validation Of The Antimalarial Pantothenamide Mmv693183., Laura E. De Vries, Patrick A. M. Jansen, Catalina Barcelo, Justin Munro, Julie M. J. Verhoef, Charisse Flerida A. Pasaje, Kelly Rubiano, Josefine Striepen, Nada Abla, Luuk Berning, Judith M. Bolscher, Claudia Demarta-Gatsi, Rob W. M. Henderson, Tonnie Huijs, Karin M J Koolen, Patrick K. Tumwebaze, Tomas Yeo, Anna C. C. Aguiar, Iñigo Angulo-Barturen, Alisje Churchyard, Jake Baum, Benigno Crespo Fernández, Aline Fuchs, Francisco-Javier Gamo, Rafael V. C. Guido, María Belén Jiménez-Diaz, Dhelio B. Pereira, Rosemary Rochford, Camille Roesch, Laura M. Sanz, Graham Trevitt, Benoit Witkowski, Sergio Wittlin, Roland A. Cooper, Philip J. Rosenthal, Robert W. Sauerwein, Joost Schalkwijk, Pedro H. H. Hermkens, Roger V. Bonnert, Brice Campo, David A. Fidock, Manuel Llinás, Jacquin C. Niles, Taco W. A. Kooij, Koen J. Dechering
Natural Sciences and Mathematics | Faculty Scholarship
Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient …
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., Benjamin R. Taft, Fumiaki Yokokawa, Tom Kirrane, Anne-Catherine Mata, Richard Huang, Nicole Blaquiere, Grace Waldron, Bin Zou, Oliver Simon, Subramanyam Vankadara, Wai Ling Chan, Mei Ding, Sandra Sim, Judith Straimer, Armand Guiguemde, Suresh B Lakshminarayana, Jay Prakash Jain, Christopher Bodenreider, Christopher Thompson, Christian Lanshoeft, Wei Shu, Eric Fang, Jafri Qumber, Katherine Chan, Luying Pei, Yen-Liang Chen, Hanna Schulz, Jessie Lim, Siti Nurdiana Abas, Xiaoman Ang, Yugang Liu, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Glaxosmithkline Gamo, Benigno Crespo-Fernandez, Philip J. Rosenthal, Roland A. Cooper, Patrick Tumwebaze, Anna Caroline Campos Aguiar, Brice Campo, Simon Campbell, Jürgen Wagner, Thierry T Diagana, Christopher Sarko
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., Benjamin R. Taft, Fumiaki Yokokawa, Tom Kirrane, Anne-Catherine Mata, Richard Huang, Nicole Blaquiere, Grace Waldron, Bin Zou, Oliver Simon, Subramanyam Vankadara, Wai Ling Chan, Mei Ding, Sandra Sim, Judith Straimer, Armand Guiguemde, Suresh B Lakshminarayana, Jay Prakash Jain, Christopher Bodenreider, Christopher Thompson, Christian Lanshoeft, Wei Shu, Eric Fang, Jafri Qumber, Katherine Chan, Luying Pei, Yen-Liang Chen, Hanna Schulz, Jessie Lim, Siti Nurdiana Abas, Xiaoman Ang, Yugang Liu, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Glaxosmithkline Gamo, Benigno Crespo-Fernandez, Philip J. Rosenthal, Roland A. Cooper, Patrick Tumwebaze, Anna Caroline Campos Aguiar, Brice Campo, Simon Campbell, Jürgen Wagner, Thierry T Diagana, Christopher Sarko
Natural Sciences and Mathematics | Faculty Scholarship
A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves "artemisinin-like" kill kinetics in vitro with a parasite clearance time of/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance …
Lipophilic Stinging Nettle Extracts Possess Potent Anti-Inflammatory Activity, Are Not Cytotoxic And May Be Superior To Traditional Tinctures For Treating Inflammatory Disorders., Tyler A. Johnson, Johann Sohn, Wayne D Inman, Leonard F. Bjeldanes, Keith Rayburn
Lipophilic Stinging Nettle Extracts Possess Potent Anti-Inflammatory Activity, Are Not Cytotoxic And May Be Superior To Traditional Tinctures For Treating Inflammatory Disorders., Tyler A. Johnson, Johann Sohn, Wayne D Inman, Leonard F. Bjeldanes, Keith Rayburn
Natural Sciences and Mathematics | Faculty Scholarship
Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-κB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves was also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate …
Myxobacteria Versus Sponge-Derived Alkaloids: The Bengamide Family Identified As Potent Immune Modulating Agents By Scrutiny Of Lc-Ms/Elsd Libraries., Tyler A. Johnson, Johann Sohn, Yvette M. Vaske, Kimberly N. White, Tanya L. Cohen, Helene C. Vervoort, Karen Tenney, Frederick A. Valeriote, Leonard F. Bjeldanes, Phillip Crews
Myxobacteria Versus Sponge-Derived Alkaloids: The Bengamide Family Identified As Potent Immune Modulating Agents By Scrutiny Of Lc-Ms/Elsd Libraries., Tyler A. Johnson, Johann Sohn, Yvette M. Vaske, Kimberly N. White, Tanya L. Cohen, Helene C. Vervoort, Karen Tenney, Frederick A. Valeriote, Leonard F. Bjeldanes, Phillip Crews
Natural Sciences and Mathematics | Faculty Scholarship
A nuclear factor-κB (NF-κB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC-MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E' (13) and F' (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC, Santa Cruz repository allowed expansion of the structure activity relationship …
Development And Validation Of A Rapid Method For The Detection Of Latrunculol A In Plasma., Jiajiu Shaw, Frederick A. Valeriote, Joseph Media, Tyler A. Johnson, Taro Amagata, Karen Tenney, Phillip Crews
Development And Validation Of A Rapid Method For The Detection Of Latrunculol A In Plasma., Jiajiu Shaw, Frederick A. Valeriote, Joseph Media, Tyler A. Johnson, Taro Amagata, Karen Tenney, Phillip Crews
Natural Sciences and Mathematics | Faculty Scholarship
Latrunculol A is a recently discovered 6,7-dihydroxy analog of the potent actin inhibitor latrunculin A. Latrunculol A has exhibited greater cytotoxicity than latrunculin A against both murine and human colon tumor cell lines in vitro. Currently, there are no reports regarding the bioavailability of latrunculol A in vivo. This study was undertaken as a prelude to pharmacokinetic assessments and it is the first work where bioavailability of latrunculol A was studied. In the present work, a simple plasma preparation and a rapid HPLC method have been developed. Mouse plasma containing latrunculol A was first treated by acetonitrile and then centrifuged …