Article
Biochemistry & Molecular Biology
Ines Paccetti-Alves, Marta S. P. Batista, Catarina Pimpao, Bruno L. Victor, Graca Soveral
Summary: The natural polyphenolic compound Rottlerin (RoT) has shown potential as an anticancer agent by inhibiting target molecules implicated in tumorigenesis. It has been found to inhibit human AQP3 activity with an IC50 in the micromolar range. Molecular docking and simulations have revealed the structural determinants of RoT that explain its ability to inhibit AQP3. This multidisciplinary approach provides new information for aquaporin research and future drug design.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Catarina Pimpao, Darren Wragg, Riccardo Bonsignore, Brech Aikman, Per Amstrup Pedersen, Stefano Leoni, Graca Soveral, Angela Casini
Summary: The study investigated the inhibition of glycerol permeation via human aquaporin-10 (hAQP10) by organometallic gold complexes and described its mechanism using molecular modeling and atomistic simulations. The most effective inhibitors were found to be cyclometalated Au(III) C<^>N compounds that react with cysteine residues irreversibly. Computational results from metadynamics showed that local arylation in hAQP10 by the gold inhibitors led to a global change in glycerol translocation free energy across the channel.
Article
Biochemistry & Molecular Biology
Anna M. Erian, Michael Egermeier, Hans Marx, Michael Sauer
Summary: Cellular membranes separate cells from the environment and cells developed specialized transport proteins for the transfer of metabolites across these membranes. The yeast Yarrowia lipolytica seems to favor glycerol over glucose, and this study identified six proteins in Y. lipolytica that are involved in glycerol transport. Disruption of these transporters abolished the growth of Y. lipolytica on high glycerol concentrations.
Article
Biochemistry & Molecular Biology
Eric T. Alexander, Erin Fahey, Otto Phanstiel, Susan K. Gilmour
Summary: This study found that the activation of polyamine-dependent GCN2 signaling in the tumor microenvironment plays a crucial role in tumor cell survival and immunosuppressive function. The inhibition of GCN2 can suppress polyamine metabolism and tumor growth.
Article
Virology
Jason Rodriguez, Owen Price, Rachel Jennings, Amy Creel, Sarah Eaton, Jennifer Chesnutt, Gene McClellan, Sweta R. Batni
Summary: This paper presents a robust modeling framework that considers disease transmissibility using SARS-CoV-2 as a case study. Through sensitivity analysis on the model framework, it helps advance and prioritize research efforts.
Article
Computer Science, Interdisciplinary Applications
Ayisha Mahmudova, Iacopo Borsi, Giovanni Michele Porta
Summary: This study models inhibitor injection to slow down mineral precipitation in subsurface formations, quantifying the impact of uncertainties on system outputs. Results show that treatment optimization based on single output variables may lead to high failure probability in a multi-objective framework.
COMPUTATIONAL GEOSCIENCES
(2022)
Article
Immunology
Huan Qiao, Jozef Zienkiewicz, Yan Liu, Jacek Hawiger
Summary: The global incidence of sepsis has reached nearly 49 million cases in 2017, resulting in 11 million deaths. A genomic response to sepsis has been observed in the lungs and kidneys, with thousands of genes significantly affected. However, this response can be controlled by the Nuclear Transport Checkpoint Inhibitor (NTCI), which has been shown to reduce sepsis-induced gene expression and bacterial dissemination in the lungs and spleen.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Johanna Dolensky, Clemens Hinteregger, Andreas Leitner, Werner Seebacher, Robert Saf, Ferdinand Belaj, Pascal Maser, Marcel Kaiser, Robert Weis
Summary: N-(Aminoalkyl)azabicyclo[3.2.2]nonanes with terminal tetrazole or sulfonamido partial structure were synthesized. The structures of these compounds were confirmed by various analyses. In vitro experiments showed that the sulfonamide and tetrazole derivatives exhibited significant activities against Plasmodium falciparum and Trypanosoma brucei rhodesiense.
Article
Biochemistry & Molecular Biology
Alireza Mousavi, Parham Foroumadi, Zahra Emamgholipour, Pascal Maser, Marcel Kaiser, Alireza Foroumadi
Summary: The nitro-containing compounds discovered in this study showed high activity against Trypanosoma brucei, making them potential candidates for treating sleeping sickness.
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are major causes of death and illness, particularly in low- and middle-income countries. The development of new medicines for leishmaniasis and Chagas disease is urgently needed, with limited progress in the clinical pipeline for Chagas disease. This review provides an overview of recent advances in understanding the biology of these pathogens, with a focus on drug discovery, as well as the development of new drug candidates and potential solutions to overcome challenges in clinical development.
NATURE REVIEWS MICROBIOLOGY
(2023)
Article
Multidisciplinary Sciences
Catarina A. Marques, Melanie Ridgway, Michele Tinti, Andrew Cassidy, David Horn
Summary: In this study, a genome-wide RNA-interference library screen was used to investigate the cell cycle defects in Trypanosoma brucei. The results provide comprehensive functional genomic evidence for the known and novel machineries, pathways, and regulators that coordinate trypanosome cell cycle progression.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Rachel Milne, Natalie Wiedemar, Victoriano Corpas-Lopez, Eoin Moynihan, Richard J. Wall, Alice Dawson, David A. Robinson, Sharon M. Shepherd, Robert J. Smith, Irene Hallyburton, John M. Post, Karen Dowers, Leah S. Torrie, Ian H. Gilbert, Beatriz Baragana, Stephen Patterson, Susan Wyllie
Summary: There is a need for new medicines to prevent and treat malaria. This study describes the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS), using target-focused approaches.
ACS INFECTIOUS DISEASES
(2022)
Article
Microbiology
H. J. Benns, M. Storch, J. A. Falco, F. R. Fisher, F. Tamaki, E. Alves, C. J. Wincott, R. Milne, N. Wiedemar, G. Craven, B. Baragana, S. Wyllie, J. Baum, G. S. Baldwin, E. Weerapana, E. W. Tate, M. A. Child
Summary: This study developed a CRISPR-based CORe platform to identify and prioritize electrophile-sensitive cysteines in Toxoplasma gondii for drug discovery. It was found that electrophile-sensitive cysteines on the ribosome are critical for parasite growth, leading to the identification of a parasite-selective anti-malarial lead molecule.
NATURE MICROBIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Clemens Hinteregger, Johanna Dolensky, Werner Seebacher, Robert Saf, Pascal Maeser, Marcel Kaiser, Robert Weis
Summary: 2,4-Diaminopyrimidines and (dialkylamino)azabicyclo-nonanes have activity against protozoan parasites. A series of fused hybrids were synthesized and tested in vitro against malaria tropica and sleeping sickness pathogens. The activities and selectivities of compounds strongly depended on the substitution pattern of both ring systems as well as the position of the nitrogen atom in the bicycles.
Article
Chemistry, Medicinal
Theresa Hermann, Robin Wallner, Johanna Dolensky, Werner Seebacher, Eva-Maria Pferschy-Wenzig, Marcel Kaiser, Pascal Maser, Robert Weis
Summary: The compound MMV030666 in MMV's Malaria Box exhibits multi-stage activity against various strains of Plasmodium falciparum without resistance development. By modifying the structure, a series of compounds were prepared and the relationship between the structure and activity was revealed. Furthermore, the pharmacokinetic and physicochemical parameters were improved.
Article
Multidisciplinary Sciences
Selina Bopp, Charisse Flerida A. Pasaje, Robert L. Summers, Pamela Magistrado-Coxen, Kyra A. Schindler, Victoriano Corpas-Lopez, Tomas Yeo, Sachel Mok, Sumanta Dey, Sebastian Smick, Armiyaw S. Nasamu, Allison R. Demas, Rachel Milne, Natalie Wiedemar, Victoria Corey, Maria De Gracia Gomez-Lorenzo, Virginia Franco, Angela M. Early, Amanda K. Lukens, Danny Milner, Jeremy Furtado, Francisco-Javier Gamo, Elizabeth A. Winzeler, Sarah K. Volkman, Maelle Duffey, Benoit Laleu, David A. Fidock, Susan Wyllie, Jacquin C. Niles, Dyann F. Wirth
Summary: Drug resistance to current antimalarials is increasing, necessitating the development of new drugs and targets. In this study, the authors identify Plasmodium falciparum acyl-CoA synthetase 10 as a new target, and demonstrate that its inhibition leads to a decrease in triacylglycerols. Understanding the mechanism of action of small molecules against malaria parasites can help identify new chemically validated targets.
NATURE COMMUNICATIONS
(2023)
Article
Biochemical Research Methods
Robert J. Smith, Rachel Milne, Victoriano Corpas Lopez, Natalie Wiedemar, Gourav Dey, Aisha J. Syed, Stephen Patterson, Susan Wyllie
Summary: This article presents a protocol using chemical pulldown combined with mass spectrometry (LC-MS/MS) to identify drug targets in Plasmodium falciparum. The method relies on the resin-bound inhibitor selectively binding to its molecular target(s) in cell-free lysates. The article provides a detailed description of the preparation of drug beads and P. falciparum lysate, followed by chemical pulldown, sample fractionation, and LC-MS/MS analysis. Specifically bound proteins are identified by comparing protein enrichment in DMSO-treated and drug-treated lysates using quantitative proteomics.
Article
Multidisciplinary Sciences
Srinivasa P. S. Rao, Matthew K. Gould, Jonas Noeske, Manuel Saldivia, Rajiv S. Jumani, Pearly S. Ng, Olivier Rene, Yen-Liang Chen, Marcel Kaiser, Ryan Ritchie, Amanda Fortes Francisco, Nila Johnson, Debjani Patra, Harry Cheung, Colin Deniston, Andreas D. Schenk, Wilian A. Cortopassi, Remo S. Schmidt, Natalie Wiedemar, Bryanna Thomas, Rima Palkar, Nahdiyah A. Ghafar, Vanessa Manoharan, Catherine Luu, Jonathan E. Gable, Kah Fei Wan, Elmarie Myburgh, Jeremy C. Mottram, Whitney Barnes, John Walker, Charles Wartchow, Natasha Aziz, Colin Osborne, Juergen Wagner, Christopher Sarko, John M. Kelly, Ujjini H. Manjunatha, Pascal Maeser, Jan Jiricek, Suresh B. Lakshminarayana, Michael P. Barrett, Thierry T. Diagana
Summary: Millions of people in Latin America and sub-Saharan Africa are at risk of trypanosomatid infections. Researchers have identified a class of cyanotriazoles (CTs) that have potent trypanocidal activity and can potentially be used for the treatment of Chagas disease and human African trypanosomiasis. These CT compounds act by selectively and irreversibly inhibiting trypanosomal topoisomerase II and stabilizing DNA:enzyme cleavage complexes.
Article
Microbiology
Douglas Escrivani, Viktor Scheidt, Michele Tinti, Joana Faria, David Horn
Summary: Some pathogens use antigenic variation to evade mammalian host adaptive immune responses. African trypanosomes employ variant surface glycoproteins (VSGs) to continually switch their active VSGs and avoid immune recognition. Switched trypanosomes compete in a predictable manner that is dependent on the activated VSG, and the population of cells that activates minichromosome derived VSGs has a competitive advantage.
Article
Microbiology
Anna Trenaman, Michele Tinti, Abdelmadjid Atrih, David Horn
Summary: Nucleoside analogs are widely used as anti-infective agents, but their potential as anti-parasitic agents has not been fully explored. This study identified two proteins, Tb927.6.2800 and HD82, associated with purine analog resistance in African trypanosomes. The findings also validated two nucleoside kinases involved in pro-drug activation. HD82, related to the mammalian nuclear viral restriction factor SAMHD1, sensitized trypanosomes to nucleoside analogs by reducing native nucleotide pools. This study provides insights into nucleoside/nucleotide metabolism and nucleoside analog resistance in trypanosomatids.
Review
Microbiology
Manu De Rycker, Susan Wyllie, David Horn, Kevin D. Read, Ian H. Gilbert
Summary: Leishmaniasis, Chagas disease, and human African trypanosomiasis are causing significant death and morbidity, especially in low- and middle-income countries. There is a critical need for new medications for leishmaniasis and Chagas disease, while the clinical development pipeline for Chagas disease remains sparse. This review discusses recent advancements in understanding the biology of these pathogens, with a focus on drug discovery, and explores progress in developing new drug candidates and identifying potential molecular targets. The challenges in developing new clinical candidates are also discussed, along with potential solutions to overcome these hurdles.
NATURE REVIEWS MICROBIOLOGY
(2023)