Review
Biochemistry & Molecular Biology
Evelina Moliteo, Monica Sciacca, Antonino Palmeri, Maria Papale, Sara Manti, Giuseppe Fabio Parisi, Salvatore Leonardi
Summary: There is substantial evidence that patients with cystic fibrosis (CF) have higher oxidative stress levels, which contribute to the progression of chronic lung damage. CF patients exhibit an abnormal proinflammatory environment in their airways even before infection, possibly due to elevated oxidative stress and abnormal lipid metabolism. CFTR deficiency appears to cause a redox imbalance in epithelial cells and extracellular fluids.
Review
Biochemistry & Molecular Biology
Caitlyn Harvey, Sinead Weldon, Stuart Elborn, Damian G. Downey, Clifford Taggart
Summary: The advent of CFTR modulators in cystic fibrosis treatment has transformed the management of the disease, shifting it from being a life-limiting condition to one that can be effectively managed. These genotype-specific therapies have shown significant improvements in various clinical endpoints, but their effects on pathogenic burden and airway infection need further exploration.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Charles Bengtson, Neerupma Silswal, Nathalie Baumlin, Makoto Yoshida, John Dennis, Sireesha Yerrathota, Michael Kim, Matthias Salathe
Summary: This study explored the effects of the CFTR amplifier nesolicaftor on CFTR function and ciliary beating in an inflammatory environment, demonstrating that nesolicaftor can enhance the response of F508del CFTR to the modulator ETI, and reverse the effects of TGF-beta 1 on CFTR function and cytokine expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Jia Liu, Allison P. Berg, Yiting Wang, Walailak Jantarajit, Katy J. Sutcliffe, Edward B. Stevens, Lishuang Cao, Marko J. Pregel, David N. Sheppard
Summary: This study investigates the action of a new CFTR potentiator, CP-628006, and compares it with the marketed CFTR potentiator ivacaftor. CP-628006 has distinct effects compared to ivacaftor, suggesting a different mechanism of CFTR potentiation. The emergence of CFTR potentiators with diverse modes of action makes therapy with combinations of potentiators a possibility.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Medicine, General & Internal
Hannah Farley, Sarah Poole, Stephen Chapman, William Flight
Summary: A retrospective single-center cohort study identified 19 adult patients diagnosed with CF, all of whom had a history of chronic respiratory symptoms and the majority of whom had a CFTR genotype considered eligible for CFTR modulator therapy.
POSTGRADUATE MEDICAL JOURNAL
(2022)
Review
Biochemistry & Molecular Biology
Oscar Fonseca, Maria Salome Gomes, Maria Adelina Amorim, Ana Cordeiro Gomes
Summary: Cystic fibrosis, a monogenic disease, has a diverse clinical presentation involving chronic lung infection, inflammation, and reduced bone mass. The underlying mechanisms of reduced bone mass in cystic fibrosis patients are still unclear. This review explores the relationship between CFTR dysfunction and intrinsic bone defects, as well as the impact of the proinflammatory environment and chronic infection on bone mass maintenance in CF patients.
Article
Biochemistry & Molecular Biology
Sangam Rajak, Archana Tewari, Sana Raza, Pratima Gupta, Bandana Chakravarti, Baby Anjum, Madhulika Tripathi, Brijesh K. Singh, Paul M. Yen, Amit Goel, Sujoy Ghosh, Rohit A. Sinha
Summary: Nonalcoholic steatohepatitis (NASH) is a pivotal stage in the progression of nonalcoholic fatty liver disease (NAFLD) and increases the risk of serious liver diseases. Identifying reliable molecular players in the etiology of NASH has been difficult. Furthermore, there are currently no approved drugs for NASH treatment. This study highlights the involvement of CFTR in the pathogenesis of NASH and suggests the possibility of its pharmacological inhibition in human NASH.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2023)
Article
Pharmacology & Pharmacy
L. Clara Mok, Antonio Garcia-Uceda, Matthew N. Cooper, Mariette Kemner Van De Corput, Marleen De Bruijne, Nathalie Feyaerts, Tim Rosenow, Kris De Boeck, Stephen Stick, Harm A. W. M. Tiddens
Summary: Newly developed quantitative CT outcomes designed for CF lung disease can assess structural abnormalities. CFTR modulators have the potential to reduce these abnormalities. This study aimed to investigate the effect of CFTR modulators on the progression of structural lung disease.
FRONTIERS IN PHARMACOLOGY
(2023)
Article
Chemistry, Multidisciplinary
Joshua P. Gray, Md. Nasir Uddin, Rajan Chaudhari, Margie N. Sutton, Hailing Yang, Philip Rask, Hannah Locke, Brian J. Engel, Nefeli Batistatou, Jing Wang, Brian J. Grindel, Pratip Bhattacharya, Seth T. Gammon, Shuxing Zhang, David Piwnica-Worms, Joshua A. Kritzer, Zhen Lu, Robert C. Bast, Steven W. Millward
Summary: Autophagy induction has been found to play a crucial role in the development of treatment resistance and dormancy in various cancer types. Current autophagy inhibitors, such as chloroquine and hydroxychloroquine, face challenges of poor pharmacokinetics and high toxicity at therapeutic dosages. Through the use of Scanning Unnatural Protease Resistant (SUPR) mRNA display, macrocyclic peptides targeting the autophagy protein LC3 were developed, showing promising results in sensitizing platinum-resistant ovarian cancer cells to chemotherapy. These peptides disrupted protein-protein interactions and inhibited autophagic flux, leading to significant tumor growth inhibition in mouse models of metastatic ovarian cancer.
Review
Cell Biology
Francesca Saluzzo, Luca Riberi, Barbara Messore, Nicola Ivan Lore, Irene Esposito, Elisabetta Bignamini, Virginia De Rose
Summary: Cystic Fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene, leading to imbalances in the airway microenvironment and increased susceptibility to infections. CFTR modulators have shown promise in improving airway infections, but their long-term effects remain to be fully understood.
Review
Biochemistry & Molecular Biology
Aniello Meoli, Olaf Eickmeier, Giovanna Pisi, Valentina Fainardi, Stefan Zielen, Susanna Esposito
Summary: Cystic fibrosis, a genetically inherited disease caused by mutations in the CFTR gene, is a life-threatening disorder affecting multiple systems. CFTR modulators play a crucial role in influencing and eventually restoring lung phagocyte function.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Pharmacology & Pharmacy
Margarete Olivier, Alexandra Kavvalou, Matthias Welsner, Raphael Hirtz, Svenja Strassburg, Sivagurunathan Sutharsan, Florian Stehling, Mathis Steindor
Summary: A retrospective analysis was conducted to evaluate the effects of elexacaftor/tezacaftor/ivacaftor therapy in children with cystic fibrosis. The results showed significant improvements in pulmonary function and nutritional status after 3 and 6 months of treatment. The therapy was found to be safe, although dose reductions and temporary interruptions were necessary in some cases.
FRONTIERS IN PHARMACOLOGY
(2023)
Review
Cell Biology
Lucile Regard, Clemence Martin, Esperie Burnet, Jennifer Da Silva, Pierre-Regis Burgel
Summary: Cystic fibrosis is a rare genetic multisystemic disease caused by mutations in the CFTR gene, and CFTR modulators have shown clinical efficacy in restoring CFTR protein function. However, questions remain regarding their long-term safety and effectiveness, especially in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. Further research is needed to investigate the impact of CFTR modulators on important outcomes such as concurrent treatments, lung transplantation, chest imaging, and pregnancies.
Review
Biochemistry & Molecular Biology
Renata Esposito, Davida Mirra, Giuseppe Spaziano, Francesca Panico, Luca Gallelli, Bruno D'Agostino
Summary: Cystic fibrosis (CF) is a prevalent disease with significant lung remodeling and high morbidity and mortality worldwide. Imbalance of proteases and antiproteases, particularly matrix metalloproteases (MMPs), plays a role in CF pathogenesis. While CFTR modulator therapy has shown efficacy in most CF patients, alternative experimental drugs and targeting MMPs are being explored for non-responder patients.
Article
Pharmacology & Pharmacy
Nicole Reyne, Patricia Cmielewski, Alexandra McCarron, Juliette Delhove, David Parsons, Martin Donnelley
Summary: The study evaluated the effect of lentiviral-mediated CFTR airway gene delivery on nasal PD in a CFTR knockout rat model, showing that the gene therapy resulted in a mean correction of 46% towards wild-type chloride response in treated CF rats.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Chemistry, Organic
Isabelle Wellhofer, Janina Beck, Karla Frydenvang, Stefan Brase, Christian A. Olsen
JOURNAL OF ORGANIC CHEMISTRY
(2020)
Review
Plant Sciences
Inmaculada Yruela, Carlos Moreno-Yruela, Christian A. Olsen
Summary: This review provides a comprehensive revision of plant histone deacetylase (HDA) phylogeny and translates recent lessons from other organisms. The evolution of HDAs is correlated with a gain of structural ductility/disorder, similar to other proteins. The authors highlight Brassicaceae-specific HDAs and key mutations affecting the catalytic activity of individual HDAs.
TRENDS IN PLANT SCIENCE
(2021)
Article
Multidisciplinary Sciences
Carlos Moreno-Yruela, Michael Baek, Adela-Eugenie Vrsanova, Clemens Schulte, Hans M. Maric, Christian A. Olsen
Summary: Researchers successfully captured HDAC using hydroxamic acid-modified microarray technology, providing insights into their substrate specificity and facilitating inhibitor development.
NATURE COMMUNICATIONS
(2021)
Editorial Material
Biochemistry & Molecular Biology
Maria Duca, Dennis Gillingham, Christian Adam Olsen, Gianluca Sbardella, Philip R. Skaanderup, Mario van der Stelt, Boris Vauzeilles, Olalla Vazquez, Yves P. Auberson
Summary: The EFMC is a federation of learned societies in Europe, focusing on the dynamic field spanning chemical biology and medicinal chemistry. The organization aims to drive the development of new drug candidates through the design, synthesis, and optimization of biologically active molecules.
Article
Chemistry, Multidisciplinary
Bengt H. Gless, Benjamin S. Bejder, Fabrizio Monda, Martin S. Bojer, Hanne Ingmer, Christian A. Olsen
Summary: Research has shown that pentameric AIPs presumed to contain thiolactone structures can readily rearrange into homodetic cyclopeptides, leading to implications for a better understanding of cross-species communication in bacteria and potentially guiding the discovery of peptide ligands to disrupt their function.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Multidisciplinary Sciences
Carlos Moreno-Yruela, Di Zhang, Wei Wei, Michael Baek, Wenchao Liu, Jinjun Gao, Daniela Dankova, Alexander L. Nielsen, Julie E. Bolding, Lu Yang, Samuel T. Jameson, Jiemin Wong, Christian A. Olsen, Yingming Zhao
Summary: Lysine L-lactylation is a newly discovered histone modification that is stimulated under conditions of high glycolysis. Through systematic evaluation of histone deacetylases (HDACs), HDAC1-3 and SIRT1-3 were identified as delactylases for this modification. This study provides important insights into the regulatory mechanisms of histone lactylation.
Article
Chemistry, Multidisciplinary
Nima Rajabi, Tobias N. Hansen, Alexander L. Nielsen, Huy T. Nguyen, Michael Baek, Julie E. Bolding, Oskar O. Bahlke, Sylvester E. G. Petersen, Christian R. O. Bartling, Kristian Stromgaard, Christian A. Olsen
Summary: In this study, potent small molecule inhibitors targeting SIRT5 were developed, which showed selective growth inhibition of leukemia cells in culture. This work demonstrates that masked isosteres of carboxylic acids can serve as viable chemical motifs for the development of inhibitors targeting mitochondrial enzymes, with potential applications beyond the sirtuin field.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Medicinal
Carlos Moreno-Yruela, Christian A. Olsen
Summary: This study highlights the importance of thorough kinetic investigation in the development of selective HDAC probes. Potent inhibitors of HDACs 1-3 often display slow-binding kinetics, and this study compares the potencies and selectivities of slow-binding inhibitors measured by discontinuous and continuous assays.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Multidisciplinary
Julie E. Bolding, Pablo Martin-Gago, Nima Rajabi, Luke F. Gamon, Tobias N. Hansen, Christian R. O. Bartling, Kristian Stromgaard, Michael J. Davies, Christian A. Olsen
Summary: This study demonstrates the use of aryl fluorosulfate electrophiles as covalent inhibitors targeting SIRT5, providing a potential avenue for the development of drug candidates.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2022)
Article
Chemistry, Multidisciplinary
Bengt H. Gless, Sabrina H. Schmied, Benjamin S. Bejder, Christian A. Olsen
Summary: Thioesters are energy-rich functional groups that can react in an aqueous medium due to their hydrolytic stability at neutral pH. This study investigates the reactivity of thioesters mimicking acyl-coenzyme A (CoA) species and S-acylcysteine modifications, as well as aryl thioesters used in chemical protein synthesis. The researchers developed a fluorogenic assay to directly measure the reaction rate between thioesters and nucleophiles, and found differences in the acylation ability of acetyl- and succinyl-CoA mimics. Furthermore, the study revealed the impact of tris-(2-carboxyethyl)phosphine (TCEP) on native chemical ligation reaction conditions, including potentially harmful hydrolysis side reactions.
Article
Oncology
Dongqing Yan, Anca Franzini, Anthony D. Pomicter, Brayden J. Halverson, Orlando Antelope, Clinton C. Mason, Jonathan M. Ahmann, Anna Senina, Nadeem A. Vellore, Courtney L. Jones, Matthew S. Zabriskie, Hein Than, Michael J. Xiao, Alexandria van Scoyk, Ami B. Patel, Phillip M. Clair, William L. Heaton, Shawn C. Owen, Joshua L. Andersen, Christina M. Egbert, Julie A. Reisz, Angelo D'Alessandro, James E. Cox, Kevin C. Gantz, Hannah M. Redwine, Siddharth M. Iyer, Jamshid S. Khorashad, Nima Rajabi, Christian A. Olsen, Thomas O'Hare, Michael W. Deininger
Summary: SIRT5 is crucial for the survival and growth of AML cells, regardless of genotype, by controlling key metabolic pathways. Inhibiting SIRT5 activity is detrimental to AML cells but well tolerated by healthy hematopoietic cells, making it a potential therapeutic target for AML.
BLOOD CANCER DISCOVERY
(2021)
Article
Biochemistry & Molecular Biology
Alexander L. Nielsen, Nima Rajabi, Norio Kudo, Kathrine Lundo, Carlos Moreno-Yruela, Michael Baek, Martin Fontenas, Alessia Lucidi, Andreas S. Madsen, Minoru Yoshida, Christian A. Olsen
Summary: SIRT2 is a protein deacylase enzyme that influences diverse biological functions in the cell, making it a potential drug target for neurodegenerative diseases and cancer. Researchers have developed a series of chemical probes with potent inhibitory effects on SIRT2-mediated deacetylation and demyristoylation, providing a foundation for future therapeutic development.
RSC CHEMICAL BIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kathrin S. Troelsen, Michael Baek, Alexander L. Nielsen, Andreas S. Madsen, Nima Rajabi, Christian A. Olsen
Summary: The study developed a strategy for selectively inhibiting SIRT3 in cells by incorporating mitochondria-targeting peptide sequences into inhibitor structures, demonstrating excellent mitochondrial localization in HeLa cells and target engagement through a cellular thermal shift assay. This selective inhibition showed increased acetylation of the documented SIRT3 target MnSOD in cells, indicating potential for further investigation of SIRT3 as a drug target.
RSC CHEMICAL BIOLOGY
(2021)
Article
Biochemical Research Methods
Carlos Moreno-Yruela, Christian A. Olsen
Summary: Histone deacetylases (HDACs) are enzymes that cleave post-translational e-N-acyllysine modifications. A high-throughput screening protocol is described to identify deacylase activities, with careful optimization of continuous enzyme assays to determine kinetic parameters efficiently. These techniques can aid in inhibitor assay design and provide fundamental understanding of HDAC biochemistry.
Article
Chemistry, Medicinal
Timothy Lynagh, Stephan Kiontke, Maria Meyhoff-Madsen, Bengt H. Gless, Jonas Johannesen, Sabrina Kattelmann, Anders Christiansen, Martin Dufva, Andreas H. Laustsen, Kanchan Devkota, Christian A. Olsen, Daniel Kuemmel, Stephan Alexander Pless, Brian Lohse
JOURNAL OF MEDICINAL CHEMISTRY
(2020)