Article
Virology
Wiebke Obermann, Alexandra Friedrich, Ramakanth Madhugiri, Paul Klemm, Jan Philipp Mengel, Torsten Hain, Stephan Pleschka, Hans-Guido Wendel, Roland K. Hartmann, Susanne Schiffmann, John Ziebuhr, Christin Mueller, Arnold Gruenweller
Summary: Rocaglates are a class of broad-spectrum antiviral compounds that inhibit viral protein synthesis for different RNA viruses. They have differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. The results suggest that they have the potential to be effective antiviral drugs and are unlikely to lead to the emergence of viral escape mutations.
Article
Multidisciplinary Sciences
Wiebke Obermann, Mohammad Farhan Darin Azri, Leonie Konopka, Nina Schmidt, Francesca Magari, Julian Sherman, Liliana M. R. Silva, Carlos Hermosilla, Andreas H. Ludewig, Hicham Houhou, Simone Haeberlein, Mona Yiting Luo, Irina Haecker, Marc F. Schetelig, Christoph G. Grevelding, Frank C. Schroeder, Gilbert Sei Kung Lau, Anja Taubert, Ana Rodriguez, Andreas Heine, Tiong Chia Yeo, Arnold Gruenweller, Gaspar Taroncher-Oldenburg
Summary: Inhibition of eukaryotic initiation factor 4A (eIF4A) is proposed as a strategy to combat pathogens. Rocaglates are highly specific eIF4A inhibitors, and in silico analysis identified 35 eIF4A variants that are potentially sensitive to rocaglates. In vitro assays confirmed the predicted resistance in Caenorhabditis elegans and Leishmania amazonensis, and the predicted sensitivity in Aedes sp., Schistosoma mansoni, Trypanosoma brucei, Plasmodium falciparum, and Toxoplasma gondii. These findings suggest that rocaglates could be effective against various insect, plant, animal, and human pathogens.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Sarah Wilmore, Karly-Rai Rogers-Broadway, Joe Taylor, Elizabeth Lemm, Rachel Fell, Freda K. Stevenson, Francesco Forconi, Andrew J. Steele, Mark Coldwell, Graham Packham, Alison Yeomans
Summary: Signaling through the B-cell receptor (BCR) plays a crucial role in chronic lymphocytic leukemia (CLL), with eIF4A being identified as a key regulator downstream of BCR activation. Inhibitors of eIF4A have shown promising effects in reducing global mRNA translation, as well as inhibiting the expression of oncogenes such as MYC and MCL1. This suggests that targeting eIF4A may be a potential therapeutic strategy for CLL and other B-cell malignancies, particularly those dependent on MYC and/or MCL1 for proliferation and survival.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Multidisciplinary Sciences
Sujoy Chatterjee, Shivraj M. Yabaji, Oleksii S. Rukhlenko, Bidisha Bhattacharya, Emily Waligurski, Nandini Vallavoju, Somak Ray, Boris N. Kholodenko, Lauren E. Brown, Aaron B. Beeler, Alexander R. Ivanov, Lester Kobzik, John A. Porco, Igor Kramnik
Summary: Macrophages play a crucial role in host immunity and tissue homeostasis, with different activation programs leading to distinct functions. Imbalance of M1 and M2 macrophages can perpetuate chronic inflammation. Rocaglates sensitize macrophages to combat bacterial pathogens more effectively, showing potential for immunomodulation.
Article
Oncology
Biswendu Biswas, Ramdane Guemiri, Mandy Cadix, Celine M. Labbe, Alina Chakraborty, Martin Dutertre, Caroline Robert, Stephan Vagner
Summary: The eIF4A inhibitor silvestrol selectively inhibits the translation of alternatively polyadenylated mRNAs encoding key immune-related proteins, providing a promising approach for anti-cancer therapy targeting the translation initiation complex eIF4F. Through high-throughput analysis, it has been shown that silvestrol differentially inhibits the translation of APA isoforms of various genes in T cells, highlighting the importance of considering mRNA heterogeneity in the understanding of the anti-tumor activities of eIF4A inhibitors.
Article
Biochemistry & Molecular Biology
Yuki Kito, Akinobu Matsumoto, Kazuya Ichihara, Chisa Shiraishi, Ronghao Tang, Atsushi Hatano, Masaki Matsumoto, Peixun Han, Shintaro Iwasaki, Keiichi Nakayama
Summary: Translation begins with the binding of the eIF4F complex to the 5' mRNA cap, followed by scanning ribosomes searching for the start codon in the 5' untranslated region. This study shows that the ASC-1 complex (ASCC) associates with scanning ribosomes to regulate translation initiation. Knockdown of ASCC3, a subunit of ASCC, impairs the loading and scanning dynamics of the 43S preinitiation complex, leading to reduced translation efficiency. These findings demonstrate that ASCC not only promotes dissociation of colliding 80S ribosomes but also facilitates efficient translation initiation by scanning ribosomes.
Article
Chemistry, Medicinal
Susanne Schiffmann, Sandra Gunne, Thomas Ulshoefer, Marina Henke, Luise A. Roser, Ann-Kathrin Schneider, Jindrich Cinatl, Dominique Thomas, Yannick Schreiber, Pia Viktoria Wagner, Arnold Gruenweller, Michael J. Parnham
Summary: This study characterized the safety and bioavailability profile of silvestrol, a compound effective against various viruses. Silvestrol showed good cellular uptake and stability, with cell-type-dependent cytotoxicity likely due to low expression levels of the transport protein P-glycoprotein.
Article
Pharmacology & Pharmacy
Christin Mueller, Wiebke Obermann, Nadja Karl, Hans-Guido Wendel, Gaspar Taroncher-Oldenburg, Stephan Pleschka, Roland K. Hartmann, Arnold Gruenweller, John Ziebuhr
Summary: Rocaglate CR-31-B (-) exhibits potent antiviral activity against SARS-CoV-2, inhibiting viral replication and transmission. The drug showed significant antiviral effects in cell culture models, suggesting that it may be used as a first-line antiviral intervention strategy against novel RNA virus outbreaks.
ANTIVIRAL RESEARCH
(2021)
Review
Virology
Yajuan Ren, Guizuo Wang, Dong Han
Summary: This systematic review and meta-analysis aimed to determine the efficacy of statins in hospitalized patients with COVID-19. Seven RCTs met the inclusion criteria, but there was no significant difference in mortality, length of hospital stay, ICU admission, and mechanical ventilation between the statin group and the control group. Statins may not be effective in reducing adverse outcomes in hospitalized COVID-19 patients.
JOURNAL OF MEDICAL VIROLOGY
(2023)
Article
Chemistry, Medicinal
Jenny Desantis, Beatrice Mercorelli, Marta Celegato, Federico Croci, Alessandro Bazzacco, Massimo Baroni, Lydia Siragusa, Gabriele Cruciani, Arianna Loregian, Laura Goracci
Summary: Indomethacin (INM) has shown antiviral activity against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in drug repurposing studies. Recent research indicates that the antiviral activity of INM could be attributed to its inhibition of human prostaglandin E synthase type 2 (PGES-2). This study explores the application of Proteolysis Targeting Chimeras (PROTACs) technology to develop more potent INM-derived PROTACs with anti-CoV activity, which showed a strong improvement in antiviral potency compared to INM. Molecular modelling studies suggest that human PGES-2 is a potential target of INM-based antiviral PROTACs, paving the way for the development of host-directed anti-coronavirus strategies.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Gastroenterology & Hepatology
Sanjay Pandanaboyana, John Moir, John S. Leeds, Kofi Oppong, Aditya Kanwar, Ahmed Marzouk, Ajay Belgaumkar, Ajay Gupta, Ajith K. Siriwardena, Ali Raza Haque, Altaf Awan, Anita Balakrishnan, Arab Rawashdeh, Bogdan Ivanov, Chetan Parmar, Christopher M. Halloran, Clifford Caruana, Cynthia-Michelle Borg, Dhanny Gomez, Dimitrios Damaskos, Dimitrios Karavias, Guy Finch, Husam Ebied, James K. Pine, James R. A. Skipworth, James Milburn, Javed Latif, Jeyakumar Ratnam Apollos, Jihene El Kafsi, John A. Windsor, Keith Roberts, Kelvin Wang, Krish Ravi, Maria Coats, Marianne Hollyman, Mary Phillips, Michael Okocha, Michael S. J. Wilson, Nadeem A. Ameer, Nagappan Kumar, Nehal Shah, Pierfrancesco Lapolla, Connor Magee, Bilal Al-Sarireh, Raimundas Lunevicius, Rami Benhmida, Rishi Singhal, Srinivasan Balachandra, Semra Demirli Atici, Shameen Jaunoo, Simon Dwerryhouse, Tamsin Boyce, Vasileios Charalampakis, Venkat Kanakala, Zaigham Abbas, Manu Nayar
Summary: Patients with acute pancreatitis and coexistent SARS-CoV-2 infection are at higher risk of developing severe pancreatitis, acute respiratory distress syndrome (ARDS), prolonged hospital stays, and increased 30-day mortality.
Article
Biochemistry & Molecular Biology
Mario Servulo Izidoro, Masaaki Sokabe, Nancy Villa, William C. Merrick, Christopher S. Fraser
Summary: This study reveals the mechanism by which eukaryotic initiation factors regulate the binding of eIF4F to mRNA during translation initiation. The researchers found that eIF4E binding to eIF4G generates a high-affinity conformation of the eIF4F complex for RNA, and the nucleotide-bound state of eIF4A further regulates RNA binding. They also observed that the autoinhibitory domain of eIF4G promotes a stable eIF4A-binding state, which is overcome by eIF4E binding. These findings provide insights into the dynamic interaction between eIF4F and mRNA during the scanning process.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Lalita Subedi, Stephanie Tchen, Bhakta Prasad Gaire, Bingren Hu, Kurt Hu
Summary: The novel coronavirus, SARS-CoV-2/COVID-19, has become a global pandemic, affecting people of all ages. Nutraceuticals and phytochemicals, such as vitamins C, D, E, zinc, melatonin, and other functional foods, may have potential therapeutic efficacies in fighting the threat of the COVID-19 pandemic.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Editorial Material
Pharmacology & Pharmacy
Amer Harky, Vaibhav Mishra, Daniyal Matin Ansari, Naomi Melamed
Summary: Different approaches, such as open collaboration and closed market-driven methods, can be used for drug discovery against the COVID-19 virus. In the rapidly evolving nature of this virus, organizations should collaborate with each other to ensure timely approval of satisfactory treatment.
EXPERT OPINION ON DRUG DISCOVERY
(2021)
Article
Virology
Yining Wang, Pengfei Li, Marla Lavrijsen, Yang Li, Zhongren Ma, Maikel P. Peppelenbosch, Mirza S. Baig, Qiuwei Pan
Summary: The study found that GC376 is more effective in inhibiting both SARS-CoV-2 and seasonal coronaviruses compared to boceprevir. Therefore, GC376 should be further developed as a pan-coronavirus antiviral agent. The study also emphasizes caution in interpreting in vitro data for the development of antiviral therapies.
ARCHIVES OF VIROLOGY
(2022)
Article
Multidisciplinary Sciences
Heiko Slanina, Ramakanth Madhugiri, Ganesh Bylapudi, Karin Schultheiss, Nadja Karl, Anastasia Gulyaeva, Alexander E. Gorbalenya, Uwe Linne, John Ziebuhr
Summary: The study reveals that coronavirus nsp12 has NMPylation activity, catalyzing the transfer of NMP to nsp9 and essential for virus replication. It also highlights the importance of the phosphoramidate active site in the NNE tripeptide sequence.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Virology
Massimo Palatini, Simon Franz Mueller, Michael Kirstgen, Silke Leiting, Felix Lehmann, Lena Soppa, Nora Goldmann, Christin Mueller, Kira Alessandra Alicia Theresa Lowjaga, Jorg Alber, Giuliano Ciarimboli, John Ziebuhr, Dieter Glebe, Joachim Geyer
Summary: This study identified IFITM3 as a novel protein-protein interaction partner of NTCP, which significantly affects the infection of HBV and HDV in hepatoma cells and primary human hepatocytes expressing NTCP. However, the specific mechanism by which this interaction facilitates the infection process remains unknown.
Article
Virology
Wiebke Obermann, Alexandra Friedrich, Ramakanth Madhugiri, Paul Klemm, Jan Philipp Mengel, Torsten Hain, Stephan Pleschka, Hans-Guido Wendel, Roland K. Hartmann, Susanne Schiffmann, John Ziebuhr, Christin Mueller, Arnold Gruenweller
Summary: Rocaglates are a class of broad-spectrum antiviral compounds that inhibit viral protein synthesis for different RNA viruses. They have differences in cytotoxicity against human immune cells, RNA-clamping efficiency, and antiviral activity. The results suggest that they have the potential to be effective antiviral drugs and are unlikely to lead to the emergence of viral escape mutations.
Article
Virology
Georgios-Dimitrios Panagiotidis, Christin Mueller, Marco Binder, Friedemann Weber
Summary: The FDA-approved drug paliperidone has been found to inhibit the replication of influenza A virus by interfering with the binding of the polymerase subunit PB2 to the nucleoprotein NP. However, its effects are transient and limited to specific virus strains.
ARCHIVES OF VIROLOGY
(2023)
Article
Chemistry, Medicinal
Santo Previti, Roberta Ettari, Elsa Calcaterra, Salvatore Di Maro, Stefan J. Hammerschmidt, Christin Mueller, John Ziebuhr, Tanja Schirmeister, Sandro Cosconati, Maria Zappala
Summary: Despite progress in the development of vaccines and antivirals, the fight against SARS-CoV-2 and COVID-19 continues. Researchers have identified compounds that target the SARS-CoV-2 main protease, an essential viral enzyme, and have developed inhibitors with promising antiviral activity. These inhibitors also showed inhibitory effects on hCatL, a protein involved in viral entry into host cells. Some of these compounds demonstrated significant activity against SARS-CoV-2 in cell culture.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Letter
Multidisciplinary Sciences
Mohammed Samer Shaban, Christin Mueller, Christin Mayr-Buro, Hendrik Weiser, M. Lienhard Schmitz, John Ziebuhr, Michael Kracht
NATURE COMMUNICATIONS
(2022)
Article
Microbiology
David Scheibner, Ahmed H. Salaheldin, Ola Bagato, Luca M. Zaeck, Ahmed Mostafa, Ulrike Blohm, Christin Mueller, Ahmed F. Eweas, Kati Franzke, Axel Karger, Alexander Schaefer, Marcel Gischke, Donata Hoffmann, Solene Lerolle, Xuguang Li, Hatem S. Abd El-Hamid, Jutta Veits, Angele Breithaupt, Geert-Jan Boons, Mikhail Matrosovich, Stefan Finke, Stephan Pleschka, Thomas C. Mettenleiter, Robert P. de Vries, Elsayed M. Abdelwhab
Summary: Mutations in the neuraminidase (NA) of human H5N1 viruses play different roles in infection of mammals without affecting virulence or transmission in chickens. This study is important to understand the genetic determinants for replication of avian influenza viruses in mammals and should assist in the prediction of avian influenza viruses with zoonotic potential.
Article
Microbiology
Dayly Mashaal, Sara H. Mahmoud, Christin Mueller, Noura M. Abo Shama, Amal Abo Kamer, Ahmed A. Abdelaziz, Mohamed A. Ali, Stephan Pleschka, Ahmed Mostafa
Summary: Avian influenza virus (AIV) H9N2 is endemic in birds in the Middle East, particularly in Egypt, with multiple cases of human infections. Adaptive amino acid mutations in the viral polymerase, specifically in the PB2 gene, can enhance cross-species transmission of the virus. The presence of 591K in the PB2 gene of H9N2 strains in Egypt significantly increases the replication efficiency and polymerase activity of H5N1 variants in mammalian cells.
Article
Virology
Heiko Slanina, Ramakanth Madhugiri, Kai Wenk, Tess Reinke, Karin Schultheiss, Julia Schultheis, Nadja Karl, Uwe Linne, John Ziebuhr
Summary: The coronavirus replication-transcription complex (RTC) is essential for coronavirus genome replication and expression. The central functional subunit of RTC is nsp12, which contains the RNA-directed RNA polymerase (RdRp) domain and NiRAN domain. In this study, the NiRAN-mediated NMPylation activities of alpha- and betacoronaviruses were investigated and compared. The study revealed conserved properties of NiRAN domains, including robust NMPylation activities, nucleotide substrate preference, dependence on divalent metal ions, and the critical role of N-terminal residues for efficient NMPylation.
JOURNAL OF VIROLOGY
(2023)
Article
Virology
Felix Lehmann, Heiko Slanina, Martin Roderfeld, Elke Roeb, Jonel Trebicka, John Ziebuhr, Wolfram H. Gerlich, Christian G. Schuettler, Bernhard Schlevogt, Dieter Glebe
Summary: Chronic hepatitis B virus (HBV) infection is a global health threat. Mutations in the surface antigen of HBV (HBsAg) may alter its antigenicity, infectivity, and transmissibility. A patient positive for HBV DNA and detectable but low-level HBsAg in parallel with anti-HBs suggested the presence of immune and/or diagnostic escape variants. Secreted HBsAg was also subjected to four widely used, state-of-the-art diagnostic assays, which all failed to detect the hyperglycosylated insertion variant. Additionally, the recognition of mutant HBsAg by vaccine- and natural infection-induced anti-HBs antibodies was severely impaired.
Article
Neurosciences
James T. Morton, Dong-Min Jin, Robert H. Mills, Yan Shao, Gibraan Rahman, Daniel McDonald, Qiyun Zhu, Metin Balaban, Yueyu Jiang, Kalen Cantrell, Antonio Gonzalez, Julie Carmel, Linoy Mia Frankiensztajn, Sandra Martin-Brevet, Kirsten Berding, Brittany D. Needham, Maria Fernanda Zurita, Maude David, Olga V. Averina, Alexey S. Kovtun, Antonio Noto, Michele Mussap, Mingbang Wang, Daniel N. Frank, Ellen Li, Wenhao Zhou, Vassilios Fanos, Valery N. Danilenko, Dennis P. Wall, Paul Cardenas, Manuel E. Baldeon, Sebastien Jacquemont, Omry Koren, Evan Elliott, Ramnik J. Xavier, Sarkis K. Mazmanian, Rob Knight, Jack A. Gilbert, Sharon M. Donovan, Trevor D. Lawley, Bob Carpenter, Richard Bonneau, Gaspar Taroncher-Oldenburg
Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by diverse cognitive, behavioral, and communication impairments. This study proposes a framework using Bayesian differential ranking algorithm to identify ASD-associated molecular and taxa profiles across various datasets. The findings suggest a functional architecture in the gut-brain axis (GBA) that correlates with ASD phenotypes and involves microbial species in specific genera. Additionally, temporal changes in the microbiome composition were strongly associated with ASD phenotypes.
NATURE NEUROSCIENCE
(2023)