Review
Biochemistry & Molecular Biology
Patricia Martins-Dias, Luisa Romao
Summary: Nonsense mutations can lead to dysfunctional proteins, but nonsense suppression therapy has the potential to restore protein function and treat a variety of genetic disorders. However, the efficiency of suppression may be influenced by nonsense-mediated decay, highlighting the importance of using NMD inhibitors or readthrough-compound potentiators to enhance therapeutic effects.
CELLULAR AND MOLECULAR LIFE SCIENCES
(2021)
Article
Multidisciplinary Sciences
Laure Bidou, Olivier Bugaud, Goulven Merer, Matthieu Coupet, Isabelle Hatin, Egor Chirkin, Sabrina Karri, Stephane Demais, Pauline Francois, Jean-Christophe Cintrat, Olivier Namy
Summary: In this study, a new drug was developed and evaluated for its clinical potential in treating genetic diseases caused by premature termination codons (PTCs). The drug, TLN468, was found to be more effective than the currently used gentamicin and acted on a broader range of sequences without affecting normal stop codon readthrough.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Article
Chemistry, Medicinal
Sandip Guchhait, Alina Khononov, Tomasz Pienko, Valery Belakhov, Timor Baasov
Summary: New derivatives of aminoglycosides with a 1,2-aminoalcohol side chain at the 5 position of ring III were synthesized and evaluated. Compound 6, a novel lead structure, showed enhanced selectivity towards eukaryotic ribosomes, high readthrough activity, and lower toxicity compared to previous compounds. Molecular dynamics simulations revealed the kinetic stability of compound 6 within the A site of the 80S yeast ribosome, which potentially contributes to its high readthrough activity.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Venkateshwar Mutyam, Jyoti Sharma, Yao Li, Ning Peng, Jianguo Chen, Li Ping Tang, Emily Falk Libby, Ashvani K. Singh, Katja Conrath, Steven M. Rowe
Summary: Premature-termination codons (PTCs) in the CFTR gene lead to nonfunctional CFTR protein, accounting for 11% of CF-causing alleles with no current effective treatments. Novel CFTR correctors and potentiators show comparable effects to existing ones in vitro, and their combination can enhance the improvement of CFTR function with terminal PTC mutations.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2021)
Article
Multidisciplinary Sciences
Jyoti Sharma, Ming Du, Eric Wong, Venkateshwar Mutyam, Yao Li, Jianguo Chen, Jamie Wangen, Kari Thrasher, Lianwu Fu, Ning Peng, Liping Tang, Kaimao Liu, Bini Mathew, Robert J. Bostwick, Corinne E. Augelli-Szafran, Hermann Bihler, Feng Liang, Jerome Mahiou, Josef Saltz, Andras Rab, Jeong Hong, Eric J. Sorscher, Eric M. Mendenhall, Candice J. Coppola, Kim M. Keeling, Rachel Green, Martin Mense, Mark J. Suto, Steven M. Rowe, David M. Bedwell
Summary: In this study, compounds with readthrough activity were identified and shown to reduce premature termination associated with cystic fibrosis by lowering eRF1 levels. These compounds, including SRI-41315 and SRI-37240, have potential as promising treatment strategies for diseases caused by PTCs.
NATURE COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Daniel R. McHugh, Calvin U. Cotton, Craig A. Hodges
Summary: This study demonstrated synergy between NMD inhibitors and readthrough agents in increasing functional protein quantity following readthrough, suggesting a potential therapeutic option for treating nonsense mutations.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Chemistry, Medicinal
Christie Morrill, Westley J. Friesen, Suresh Babu, Ramil Y. Baiazitov, Wu Du, Diane B. Karloff, Chang -Sun Lee, Young-Choon Moon, Hongyu Ren, Jairo Sierra, Yuki Tomizawa, Priya Vazirani, Ellen M. Welch, Xiaojiao Xue, Jin Zhuo
Summary: Using small molecules to induce readthrough is an effective method for treating genetic diseases and cancers. This study introduces a series of novel compounds that show potential for inducing readthrough in cells, either as combination therapy or standalone treatment.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Biochemistry & Molecular Biology
Mikel D. D. Ghelfi, Saleem Y. Y. Bhat, Hong Li, Barry S. S. Cooperman
Summary: The research findings show that Ataluren acts as a competitive inhibitor, blocking the catalytic function of the release factor complex (RFC) and inducing readthrough. This opens up the possibility of discovering new readthrough-inducing drugs that are both low in toxicity and more effective at stimulating readthrough.
Article
Biochemistry & Molecular Biology
Maciej Dabrowski, Zuzanna Bukowy-Bieryllo, Claire L. Jackson, Ewa Zietkiewicz
Summary: The study identified several non-aminoglycoside compounds with potential to induce PTC-readthrough, which demonstrated minimal negative impact on cell viability and function compared to aminoglycosides, although with lower efficiency.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biology
Martine Palma, Fabrice Lejeune
Summary: Recognition of the stop codon is crucial for terminating translation and synthesizing the correct size protein. Stop codon readthrough can occur under specific conditions, leading to different protein isoforms, and has potential therapeutic implications for genetic diseases caused by nonsense mutations.
BIOLOGICAL REVIEWS
(2021)
Review
Cell Biology
Joseph J. Porter, Christina S. Heil, John D. Lueck
Summary: Nonsense mutations create defective truncated proteins by changing amino acid codons. While most PTC therapeutics focus on promoting PTC read-through, there is a need for agents that can recode PTCs with the correct amino acids.
WILEY INTERDISCIPLINARY REVIEWS-RNA
(2021)
Article
Medicine, Research & Experimental
Federica Corrao, Maria Grazia Zizzo, Marco Tutone, Raffaella Melfi, Ignazio Fiduccia, Pietro Salvatore Carollo, Aldo Di Leonardo, Gaetano Caldara, Riccardo Perriera, Andrea Pace, Beatrice Belmonte, Selene Sammataro, Ivana Pibiri, Laura Lentini
Summary: This study investigated the acute toxicological effects of three Translational Readthrough Inducing Drugs (TRIDs) on mice and found that these drugs showed good tolerability without causing significant adverse effects in the mice.
BIOMEDICINE & PHARMACOTHERAPY
(2022)
Article
Pharmacology & Pharmacy
Renata B. V. Abreu, Thiago T. Gomes, Thales C. Nepomuceno, Xueli Li, Mateus Fuchshuber-Moraes, Giuliana De Gregoriis, Guilherme Suarez-Kurtz, Alvaro N. A. Monteiro, Marcelo A. Carvalho
Summary: This study evaluates the readthrough of clinically relevant PTC variants in the breast and ovarian cancer-predisposing gene BRCA1 for the first time, demonstrating that the aminoglycoside G418 can induce PTC readthrough and restore full-length protein synthesis and function.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Physiology
Jianguo Chen, Kari Thrasher, Lianwu Fu, Wei Wang, Soheil Aghamohammadzadeh, Hui Wen, Liping Tang, Kim M. Keeling, Emily Falk Libby, David M. Bedwell, Steven M. Rowe
Summary: In this study, it was found that G550X-CFTR patient-derived intestinal organoids had significantly higher swelling after treatment with ELX-02 compared to G542X-CFTR organoids. Tryptophan was the only amino acid inserted in the G550X position after readthrough. The resulting G550W-CFTR protein exhibited supernormal CFTR activity, PKA sensitivity, and open probability. These results indicate that aminoglycoside-induced readthrough of G550X produces greater CFTR function due to the gain-of-function properties of the CFTR readthrough product.
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Roland N. Wagner, Michael Wiessner, Andreas Friedrich, Johanna Zandanell, Hannelore Breitenbach-Koller, Johann W. Bauer
Summary: This review summarizes the current understanding of translation termination and highlights newly discovered pathways that influence its fidelity. It also describes the mechanisms involved in the recognition and readthrough of premature termination codons (PTCs) and reports on compounds that induce PTC readthrough. The ongoing attempts of personalized nonsense suppression therapy in different disease contexts are also reviewed.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Multidisciplinary
Evan R. McCarney, Carol J. Breaux, Phillip M. Rendle
MAGNETIC RESONANCE IN CHEMISTRY
(2020)
Article
Chemistry, Medicinal
Rinu Shrestha, Emma V. Petley, Kathryn J. Farrand, Sam A. Jamieson, Wanting Jiao, Paul H. Teesdale-Spittle, Peter D. Mace, Ian F. Hermans, Phillip M. Rendle
Article
Chemistry, Multidisciplinary
Rinu Shrestha, Paul H. Teesdale-Spittle, Andrew R. Lewis, Phillip M. Rendle
Article
Chemistry, Multidisciplinary
Georgia M. Richardson, Iskander Douair, Scott A. Cameron, Laurent Maron, Mathew D. Anker
Summary: The dimeric beta-diketiminato ytterbium(II) hydride can act as a powerful two-electron reductant at room temperature, affecting the reactions of polyaromatic hydrocarbons such as naphthalene without the need for external electron involvement.
CHEMISTRY-A EUROPEAN JOURNAL
(2021)
Article
Biochemistry & Molecular Biology
Michael J. Currie, Lavanyaa Manjunath, Christopher R. Horne, Phillip M. Rendle, Ramaswamy Subramanian, Rosmarie Friemann, Antony J. Fairbanks, Andrew C. Muscroft-Taylor, Rachel A. North, Renwick C. J. Dobson
Summary: The study found that the enzyme NanE may use a novel substrate-assisted proton displacement mechanism for catalysis, by re-evaluating the central role of Glu180 and the catalytic lysine, and identifying several active-site residues related to the mechanism. This discovery could be helpful in developing inhibitors for the enzyme or producing biocatalysts capable of changing the stereochemistry of molecules through enzyme engineering.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Chemistry, Organic
James M. Wood, Gary B. Evans, Tyler L. Grove, Steven C. Almo, Scott A. Cameron, Richard H. Furneaux, Lawrence D. Harris
Summary: ddhCTP is a novel antiviral molecule that acts as a chain terminator of flavivirus and SARS-CoV-2 RNA-dependent RNA polymerases. Limited access to this promising antiviral has hindered further biophysical studies, but a robust synthesis method has been developed to prepare ddhCTP on a gram scale.
JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Georgia M. Richardson, Iskander Douair, Scott A. Cameron, Joe Bracegirdle, Robert A. Keyzers, Michael S. Hill, Laurent Maron, Mathew D. Anker
Summary: Nucleophilic alkylation of aromatics with main group reagents is limited to a stoichiometric regime. The ytterbium(II) hydride reacts with ethene and propene to form ytterbium(II) n-alkyls, which can catalyze the alkylation of benzene at room temperature through an S(N)2 mechanism.
NATURE COMMUNICATIONS
(2021)
Article
Chemistry, Multidisciplinary
Andreas Luxenburger, Lawrence D. Harris, Elizabeth M. Ure, Roselis A. Landaeta Aponte, Anthony D. Woolhouse, Scott A. Cameron, Chris D. Ling, Ross O. Piltz, Andrew R. Lewis, Graeme J. Gainsford, Alex Weymouth-Wilson, Richard H. Furneaux
Summary: Decoupling the roles of the farnesoid X nuclear receptor and the Takeda G-protein-coupled bile acid receptor 5 is crucial for developing novel bile acid therapeutics targeting metabolic and neurodegenerative diseases. The synthesis of 12 beta-methyl-18-nor-bile acids as probes for new bile acid analogues with clinical applicability was described, along with the mechanism insights provided by deuteration experiments. Optimization of the synthetic sequence enabled a chromatography-free route to prepare these bile acids at a multi-gram scale, highlighting the potential for future therapeutic developments.
Article
Biochemistry & Molecular Biology
Tanzeel Arif, Michael J. Currie, Renwick C. J. Dobson, Harriet L. Newson, Vivek Poonthiyil, Antony J. Fairbanks, Rachel A. North, Phillip M. Rendle
Summary: The synthesis of analogues of natural enzyme substrates can help deduce enzymatic mechanisms, as demonstrated by the investigation into N-acetylmannosamine-6-phosphate 2-epimerase. The study suggests that this enzyme may utilize a substrate-assisted proton displacement mechanism, with two novel analogues showing different binding orientations at the enzyme's active site.
CARBOHYDRATE RESEARCH
(2021)
Article
Chemistry, Medicinal
Andreas Luxenburger, Nicola Bougen-Zhukov, Michael G. Fraser, Henry Beetham, Lawrence D. Harris, Dorian Schmidt, Scott A. Cameron, Parry J. Guilford, Gary B. Evans
Summary: By synthesizing and testing 63 analogues, AL-GDa62 was identified as a compound with higher cytotoxicity and better selectivity against CDH1-deficient cells at low micromolar concentrations. Additionally, AL-GDa62 preferentially induced apoptosis in CDH1-deficient cells and exhibited increased sensitivity towards CDH1-deficient organoids.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Drake M. Mellott, Dan Torres, Inna Krieger, Scott A. Cameron, Zahra Moghadamchargari, Arthur Laganowsky, James C. Sacchettini, Thomas D. Meek, Lawrence D. Harris
Summary: The research shows that 5-NIC can serve as an effective inactivator of ICL1. Its design aims to lower the overall charge for improved cell permeability, facilitating the synthesis of pro-drug forms for M. tuberculosis cell-infection models.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2021)
Article
Chemistry, Multidisciplinary
Sam Spijkers-Shaw, Katrin Campbell, Nicholas J. Shields, John H. Miller, Phillip M. Rendle, Wanting Jiao, Sarah L. Young, Olga Zubkova
Summary: The synthesis and testing of a novel library of single entity trimer glycolipid mimetics that effectively inhibit HPSE at low nanomolar concentrations are reported. Preclinical tests showed that these mimetics can effectively inhibit tumor growth at low concentrations.
CHEMISTRY-AN ASIAN JOURNAL
(2022)
Article
Biochemistry & Molecular Biology
Roselis A. Landaeta Aponte, Andreas Luxenburger, Scott A. Cameron, Alex Weymouth-Wilson, Richard H. Furneaux, Lawrence D. Harris, Benjamin J. Compton
Summary: Bile acid receptors are important targets for treating metabolic and inflammatory diseases. Synthesizing new bile acid analogues helps understand their structure-activity relationships and identify selective receptor activators. In this study, a chenodeoxycholic acid derivative with specific modifications was used to explore the chemical manipulation of bile acids. Different reaction outcomes were observed when treating this derivative with different zinc carbenoid species. Further modifications and evaluations were made to these derivatives for biological purposes.