Article
Chemistry, Multidisciplinary
Fandi Sutanto, Shabnam Shaabani, Rick Oerlemans, Deniz Eris, Pravin Patil, Mojgan Hadian, Meitian Wang, May Elizabeth Sharpe, Matthew R. Groves, Alexander Domling
Summary: This study demonstrates the interplay between high throughput synthesis and high throughput PX, showing the potential of this approach in early drug discovery and successfully yielding potent inhibitors of the COVID-19 causing agent.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Medicinal
Julita Chlebowicz, Radha Akella, John M. Humphreys, Haixia He, Ashari R. Kannangara, Shuguang Wei, Bruce Posner, Elizabeth J. Goldsmith
Summary: In this study, novel WNK1 kinase inhibitors were identified and characterized. Five classes of compounds were found to strongly inhibit the kinase activity of WNK1, showing pan-WNK selectivity. Among these compounds, a class of quinoline compounds exhibited stronger inhibition towards WNK3 than WNK1. The discovery of these compounds has potential for the development of drugs and pharmacological tools for hypertension and cancer treatment.
DRUG DESIGN DEVELOPMENT AND THERAPY
(2023)
Article
Biochemistry & Molecular Biology
Felix Langschied, Matthias S. Leisegang, Ralf P. Brandes, Ingo Ebersberger
Summary: Researchers have developed a method for detecting miRNA orthologs in unannotated genome sequences. By matching miRNA annotations from multi-tissue transcriptomes, they reveal the transmission and evolution of miRNA orthologs across different species. This has important implications for understanding the evolution of miRNAs and their associated regulatory networks.
NUCLEIC ACIDS RESEARCH
(2023)
Article
Biochemistry & Molecular Biology
Ying Yu, Junsong Guo, Zhengjun Cai, Yingchen Ju, Jun Xu, Qiong Gu, Huihao Zhou
Summary: This study utilized fragment screening and X-ray crystallography to identify new building blocks and binding mechanisms for the discovery of new GyrB inhibitors. Some chemical fragments were found to affect enzyme activity, providing new insights for the design of GyrB inhibitors.
BIOORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Rui Zhang, Caili Qiao, Qiuyan Liu, Jingwen He, Yifan Lai, Jing Shang, Hui Zhong
Summary: The study suggests that using zebrafish models in screening for antidepressants can replace rodents, with similarities in behavior and pathology. This could help shorten the drug screening cycle and achieve high-throughput screening.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Multidisciplinary Sciences
Tristan O. C. Kwan, Amy E. Danson, Pascelle Draper, Paul Reardon, Isabel Moraes
Summary: Understanding the structure-function relationships of macromolecules is crucial for biomedicine and drug discovery. X-ray crystallography is the most successful method for solving protein structures at atomic resolution. Recent advances in serial crystallography allow time-resolved data acquisition and provide mechanistic insights into biological molecules at room temperature.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2023)
Article
Biochemistry & Molecular Biology
Yuguang Zhao, William Mahy, Nicky J. Willis, Hannah L. Woodward, David Steadman, Elliott D. Bayle, Benjamin N. Atkinson, James Sipthorp, Luca Vecchia, Reinis R. Ruza, Karl Harlos, Fiona Jeganathan, Stefan Constantinou, Artur Costa, Svend Kjaer, Magda Bictash, Patricia C. Salinas, Paul Whiting, Jean-Paul Vincent, Paul Fish, E. Yvonne Jones
Summary: Notum is a promising target for treating osteoporosis, Alzheimer's disease, and colorectal cancer. Through fragment screening and optimization, researchers have obtained a series of potential Notum inhibitors.
ACS CHEMICAL NEUROSCIENCE
(2022)
Article
Multidisciplinary Sciences
Gabrielle R. Budziszewski, M. Elizabeth Snell, Tiffany R. Wright, Miranda L. Lynch, Sarah E. J. Bowman
Summary: X-ray crystallography is commonly used to study macromolecular structures, but the process of crystallizing a protein for analysis is difficult. The National High-Throughput Crystallization (HTX) Center has developed reproducible methods for crystal growth, including an automated system to test a wide range of crystallization parameters. Imaging techniques are used to monitor the growth of crystals over a 6-week period and an artificial intelligence algorithm is used to identify valuable crystals. The implementation of this system streamlines the analysis of crystal growth images and increases the chances of successful crystallization.
JOVE-JOURNAL OF VISUALIZED EXPERIMENTS
(2023)
Article
Biochemical Research Methods
Miranda L. Lynch, M. Elizabeth Snell, Stephen A. Potter, Edward H. Snell, Sarah E. J. Bowman
Summary: Diffraction-based structural methods have contributed significantly to biomolecular structural models, playing a critical role in understanding macromolecular architecture. Despite being a primary bottleneck, the National High-Throughput Crystallization Center at Hauptman-Woodward Medical Research Institute has made efforts to overcome crystallization obstacles through robotics-enabled high-throughput screening and advanced imaging. This paper discusses the lessons learned from over 20 years of operation, detailing experimental pipelines, instrumentation, imaging capabilities, and software for crystal scoring. It also reflects on new developments in the field and opportunities for further improvement in biomolecular crystallization.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Yihuang Xiong, Celine Bourgois, Natalya Sheremetyeva, Wei Chen, Diana Dahliah, Hanbin Song, Jiongzhi Zheng, Sinead M. Griffin, Alp Sipahigil, Geoffroy Hautier
Summary: This study uses first-principles computational screening to identify potential spin-photon interfaces in silicon, paving the way for finding suitable quantum defects.
Article
Chemistry, Medicinal
Andrea Dalle Vedove, Giulia Cazzanelli, Laurent Batiste, Jean-Remy Marchand, Dimitrios Spiliotopoulos, Jessica Corsi, Vito Giuseppe D'Agostino, Amedeo Caflisch, Graziano Lolli
Summary: BAZ2A is an epigenetic regulator that affects transcription of ribosomal RNA and is overexpressed in aggressive prostate cancer. A structure-based fragment-growing campaign has identified ligands for the BAZ2A bromodomain, with some compounds showing enantiospecific binding and good selectivity. Interaction with the side chain of Glu1820 is crucial for ligand binding efficacy.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Engineering, Electrical & Electronic
Arafat Al-Dweik, Youssef Iraqi
Summary: The study introduces a new framework called non-orthogonal multiplexing (NOM) which utilizes power domain multiplexing to enhance the throughput of wireless sensor network applications. By combining multiple data packets and transmitting them simultaneously, the system throughput is increased and transmission delay is reduced. Additionally, a simple protocol is employed to overcome the limitations of channel state information feedback.
IEEE SENSORS JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Tristan O. C. Kwan, Stefan A. Kolek, Amy E. Danson, Rosana Reis, Ines S. Camacho, Patrick D. Shaw Stewart, Isabel Moraes
Summary: The structure-function relationships of biological macromolecules, especially proteins, are crucial for fundamental biochemistry, medical research, and early drug discovery. However, improving protein stability and reducing aggregation remains a challenging task.
FRONTIERS IN MOLECULAR BIOSCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ankita Arora, Roberto Castro-Gutierrez, Charlie Moffatt, Davide Eletto, Raquel Becker, Maya Brown, Andreas E. Moor, Holger A. Russ, J. Matthew Taliaferro
Summary: The study reveals that there are numerous RNAs enriched in the projections of neuronal cells, and identifies sequence elements that regulate their localization. These localization elements are enriched in adenosine and guanosine residues, and are tens to hundreds of nucleotides long. The RNA-binding protein Unk is associated with these localization elements and is functionally required for RNA trafficking to neurites.
NUCLEIC ACIDS RESEARCH
(2022)
Article
Biochemical Research Methods
Connor S. Dobson, Anna N. Reich, Stephanie Gaglione, Blake E. Smith, Ellen J. Kim, Jiayi Dong, Larance Ronsard, Vintus Okonkwo, Daniel Lingwood, Michael Dougan, Stephanie K. Dougan, Michael E. Birnbaum
Summary: Deciphering immune recognition is crucial for understanding diseases and developing vaccines and immunotherapies. However, current technologies lack the capability to capture the complexity of immune receptor repertoires and potential antigens simultaneously, limiting research progress. RAPTR combines viral pseudotyping and molecular engineering to enable interaction screens between antigens and immune receptors, providing a suite of tools with broad applications.
Article
Biochemistry & Molecular Biology
Piotr Wilk, Elzbieta Wator, Manfred S. Weiss
Summary: Prolidase is a metal-dependent peptidase specialized in cleaving dipeptides containing proline or hydroxyproline. Its importance in human health is increasingly recognized, especially in rare hereditary syndromes and cancer. In addition, prolidase has an activity-independent regulatory role and applications in biotechnology.
Article
Chemistry, Medicinal
Ah Young Park, Imane Nafia, Damien N. Stringer, Samuel S. Karpiniec, J. Helen Fitton
Summary: Fucoidan compounds were found to promote proliferation and activity of immune cells and enhance the effects of the immune-checkpoint inhibitor drug Nivolumab. Additionally, these compounds directly inhibited the growth of prostate cancer cells but did not increase their cell killing activity.
Article
Chemistry, Medicinal
Tauseef Ahmad, Mathew Suji Eapen, Muhammad Ishaq, Ah Young Park, Samuel S. Karpiniec, Damien N. Stringer, Sukhwinder Singh Sohal, J. Helen Fitton, Nuri Guven, Vanni Caruso, Rajaraman Eri
Summary: Fucoidan extracts from various species of brown seaweeds have significant anti-inflammatory effects and can reduce inflammation-related pathologies by inhibiting inflammatory processes. Different fucoidan extracts have a modulating effect on the production of inflammatory cytokines, with lower molecular weight subfractions showing maximal effects at low concentrations.
Article
Biochemical Research Methods
Frank Lennartz, Jae Hun Jeoung, Stefan Ruenger, Holger Dobbek, Manfred S. Weiss
Summary: Protein-mediated redox reactions are crucial in biological processes, often occurring at metal ion centers. Spatially resolved anomalous dispersion (SpReAD) refinement is a suitable method for characterizing the oxidation states of cofactors and their structures. In this study, SpReAD analysis was applied to a ruberythrin-like protein, revealing differences in oxidation states of individual iron ions in a binuclear metal center.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Maria-Elena Liosi, Joseph A. Ippolito, Sean P. Henry, Stefan G. Krimmer, Ana S. Newton, Kara J. Cutrona, Rene A. Olivarez, Jyotidarsini Mohanty, Joseph Schlessinger, William L. Jorgensen
Summary: This study aimed to develop binders that selectively target the JH2 domain of JAK2 and test their ability to modulate JAK2 activity in cells. Through computational design, synthesis, binding affinity measurements, permeability measurements, crystallography, and cell assays, the researchers successfully optimized a diaminotriazole compound that can inhibit the activity of JAK2 in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Sean P. Henry, Maria-Elena Liosi, Joseph A. Ippolito, Kara J. Cutrona, Stefan G. Krimmer, Ana S. Newton, Joseph Schlessinger, William L. Jorgensen
Summary: The study explored the potential of modulating JAK2 kinase activity by binding to the ATP site in JH2 domain and developed compounds with nanomolar affinity and high selectivity for JAK2 JH2 domain. Crystal structure analysis revealed the binding mechanism of these compounds with JAK2 JH2, offering a new platform for seeking molecules to regulate JAK2 signaling.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Food Science & Technology
Malcolm Turk Hsern Tan, Mohamad Eshaghi Gorji, Jillinda Yi Ling Toh, Ah Young Park, Yan Li, Zhiyuan Gong, Dan Li
Summary: Fucoidan extracted from Fucus vesiculosus can inhibit the replication of human noroviruses in zebrafish. Transcriptomic analysis showed that injection of fucoidan can enhance the host innate immune response, which may be one of the important mechanisms behind the anti-norovirus effect of fucoidan.
JOURNAL OF FUNCTIONAL FOODS
(2022)
Article
Biochemistry & Molecular Biology
Manfred S. Weiss, Jan Wollenhaupt, Galen J. Correy, James S. Fraser, Andreas Heine, Gerhard Klebe, Tobias Krojer, Marjolein Thunnissen, Nicholas M. Pearce
Summary: Jaskolski et al. analyzed diffraction data sets from fragment-screening group depositions and claimed that these data are problematic. However, we demonstrate that none of the criticisms persist if the data are treated properly.
Article
Chemistry, Medicinal
Tatjana Barthel, Jan Wollenhaupt, Gustavo M. A. Lima, Markus C. Wahl, Manfred S. Weiss
Summary: The identification of starting points for compound development is crucial in early-stage drug discovery. Crystallographic fragment screening provides structural information of the binding mode, increasing the efficiency of this step. In this study, crystallographic screening of a compound library was conducted, resulting in the identification of 269 hits distributed over 10 distinct binding sites on the protein-protein complex surface. The study demonstrates that hit clusters can identify known interaction sites and suggest potential additional interaction sites, thereby accelerating downstream compound optimization.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Editorial Material
Multidisciplinary Sciences
Stefan G. Krimmer, Joseph Schlessinger
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Pharmacology & Pharmacy
Tauseef Ahmad, Muhammad Ishaq, Samuel Karpiniec, Ahyoung Park, Damien Stringer, Neeraj Singh, Vishal Ratanpaul, Karen Wolfswinkel, Helen Fitton, Vanni Caruso, Rajaraman Eri
Summary: Inflammatory bowel disease (IBD) is a complex disorder characterized by inflammation of the gut, and oxidative stress (OS) plays a role in its exacerbation. Fucoidan extracts, MPF and DP-MPF, derived from brown seaweed, have shown anti-inflammatory and antioxidant effects in a mouse model of acute colitis induced by dextran sodium sulphate (DSS). These extracts improved disease activity, reduced inflammation, and restored antioxidant enzyme levels, suggesting their potential as a therapeutic strategy for IBD.
Article
Multidisciplinary Sciences
Stefan G. Krimmer, Nicole Bertoletti, Yoshihisa Suzuki, Luka Katic, Jyotidarsini Mohanty, Sheng Shu, Sangwon Lee, Irit Lax, Wei Mi, Joseph Schlessinger
Summary: The development of various cells, including hematopoietic stem cells and germ cells, relies on the receptor tyrosine kinase KIT and its ligand stem cell factor (SCF). Somatic mutations in KIT lead to several types of human cancers. Cryo electron microscopy analysis reveals that oncogenic KIT mutants exhibit distinct structural arrangements compared to wild-type KIT. The D5 region of KIT is identified as a potential target for therapeutic intervention.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemical Research Methods
Friederike T. Fuesser, Jan Wollenhaupt, Manfred S. Weiss, Daniel Kuemmel, Oliver Koch
Summary: With the increasing number of tuberculosis-related deaths and the presence of drug-resistant strains, there is an urgent need for alternative antituberculotic drugs. In this study, crystallographic fragment screening using crystals of Mycobacterium smegmatis TrxR was used to discover new binding fragments and binding sites. The results identified 56 starting points for the development of new TrxR inhibitors.
ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY
(2023)
Article
Physiology
Sally E. McBean, Jarrod E. Church, Brett K. Thompson, Caroline J. Taylor, J. H. Fitton, Damien N. Stringer, Sam S. Karpiniec, Ah Y. Park, Chris van der Poel
Summary: The study demonstrates that fucoidan supplementation for 4 weeks significantly increased muscle fiber cross-sectional area and strength in mice. However, there were no significant effects on grip strength or treadmill time to fatigue, and fucoidan did not affect muscle mass.
PHYSIOLOGICAL REPORTS
(2021)
Article
Chemistry, Multidisciplinary
Christopher J. Serpell, Ah Young Park, Carol V. Robinson, Paul D. Beer
Summary: A novel catenated system dense in cationic hydrogen bonding imidazolium units was described, showing a preference for binding of bromide over other halides under aqueous conditions, overcoming basicity and Hofmeister trends. This is the first example of an imidazolium-based catenane acting as an anion host through C-H hydrogen bonding.
CHEMICAL COMMUNICATIONS
(2021)