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Advances in Oligonucleotide Drug Delivery
REVIEWS Advances in oligonucleotide drug delivery Thomas C. Roberts 1,2 ✉ , Robert Langer 3 and Matthew J. A. Wood 1,2 ✉ Abstract | Oligonucleotides can be used to modulate gene expression via a range of processes including RNAi, target degradation by RNase H-mediated cleavage, splicing modulation, non-coding RNA inhibition, gene activation and programmed gene editing. As such, these molecules have potential therapeutic applications for myriad indications, with several oligonucleotide drugs recently gaining approval. However, despite recent technological advances, achieving efficient oligonucleotide delivery, particularly to extrahepatic tissues, remains a major translational limitation. Here, we provide an overview of oligonucleotide-based drug platforms, focusing on key approaches — including chemical modification, bioconjugation and the use of nanocarriers — which aim to address the delivery challenge. Oligonucleotides are nucleic acid polymers with the In addition to their ability to recognize specific tar- potential to treat or manage a wide range of diseases. get sequences via complementary base pairing, nucleic Although the majority of oligonucleotide therapeutics acids can also interact with proteins through the for- have focused on gene silencing, other strategies are being mation of three-dimensional secondary structures — a pursued, including splice modulation and gene activa- property that is also being exploited therapeutically. For tion, expanding the range of possible targets beyond example, nucleic acid aptamers are structured -
Targets for Antiviral Therapy of Hepatitis C
9 Targets for Antiviral Therapy of Hepatitis C Daniel Rupp, MD1,2 Ralf Bartenschlager, PhD1,2 1 Department for Infectious Diseases, Molecular Virology, University of Address for correspondence Ralf Bartenschlager, PhD, Department Heidelberg, Heidelberg, Germany for Infectious Diseases, Molecular Virology, University of Heidelberg, 2 German Centre for Infection Research, Heidelberg University Im Neuenheimer Feld 345, 69120 Heidelberg, Germany (e-mail: [email protected]). Semin Liver Dis 2014;34:9–21. Abstract Presently, interferon- (IFN-) containing treatment regimens are the standard of care for patients with hepatitis C virus (HCV) infections. Although this therapy eliminates the virus in a substantial proportion of patients, it has numerous side effects and contra- indications. Recent approval of telaprevir and boceprevir, targeting the protease residing in nonstructural protein 3 (NS3) of the HCV genome, increased therapy success when given in combination with pegylated IFN and ribavirin, but side effects are more frequent and the management of treatment is complex. This situation will change soon with the introduction of new highly potent direct-acting antivirals. They target, in Keywords addition to the NS3 protease, NS5A, which is required for RNA replication and virion ► NS3 protease assembly and the NS5B RNA-dependent RNA polymerase. Moreover, host-cell factors ► NS5A such as cyclophilin A or microRNA-122, essential for HCV replication, have been pursued ► NS5B as therapeutic targets. In this review, the authors briefly summarize the main features of ► miR-122 viral and cellular factors involved in HCV replication that are utilized as therapy targets ► cyclophilin A for chronic hepatitis C. Hepatitis C virus (HCV) infection still is a major health burden nonstructural protein 3 (NS3): boceprevir (BOC) and telap- affecting 130 to 170 million people worldwide. -
Antiviral Research 111 (2014) 53–59
Antiviral Research 111 (2014) 53–59 Contents lists available at ScienceDirect Antiviral Research journal homepage: www.elsevier.com/locate/antiviral Long-term safety and efficacy of microRNA-targeted therapy in chronic hepatitis C patients Meike H. van der Ree a, Adriaan J. van der Meer b, Joep de Bruijne a, Raoel Maan b, Andre van Vliet c, Tania M. Welzel d, Stefan Zeuzem d, Eric J. Lawitz e, Maribel Rodriguez-Torres f, Viera Kupcova g, ⇑ Alcija Wiercinska-Drapalo h, Michael R. Hodges i, Harry L.A. Janssen b,j, Hendrik W. Reesink a, a Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands b Department of Gastroenterology and Hepatology, Erasmus Medical Center, Rotterdam, The Netherlands c PRA International, Zuidlaren, The Netherlands d J.W. Goethe University Hospital, Frankfurt, Germany e The Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA f Fundacion de Investigacion, San Juan, Porto Rico g Department of Internal Medicine, Derer’s Hospital, University Hospital Bratislava, Slovakia h Medical University of Warsaw, Warsaw Hospital for Infectious Diseases, Warsaw, Poland i Santaris Pharma A/S, San Diego, USA j Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, Canada article info abstract Article history: Background and aims: MicroRNA-122 (miR-122) is an important host factor for hepatitis C virus (HCV) Received 6 June 2014 and promotes HCV RNA accumulation. Decreased intra-hepatic levels of miR-122 were observed in Revised 28 July 2014 patients with hepatocellular carcinoma, suggesting a potential role of miR-122 in the development of Accepted 29 August 2014 HCC. -
The Promise and Challenges of Developing Mirna-Based Therapeutics for Parkinson’S Disease
cells Review The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease Simoneide S. Titze-de-Almeida 1 , Cristina Soto-Sánchez 2, Eduardo Fernandez 2,3 , James B. Koprich 4, Jonathan M. Brotchie 4 and Ricardo Titze-de-Almeida 1,* 1 Technology for Gene Therapy Laboratory, Central Institute of Sciences, FAV, University of Brasilia, Brasília 70910-900, Brazil; [email protected] 2 Neuroprosthetics and Visual Rehabilitation Research Unit, Bioengineering Institute, Miguel Hernández University, 03202 Alicante, Spain; [email protected] (C.S.-S.); [email protected] (E.F.) 3 Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine—CIBER-BBN, 28029 Madrid, Spain 4 Krembil Neuroscience Centre, Toronto Western Hospital, University Health Network, Toronto, Ontario M5T 2S8, Canada; [email protected] (J.B.K.); [email protected] (J.M.B.) * Correspondence: [email protected]; Tel.: +55-61-3107-7222 Received: 11 February 2020; Accepted: 18 March 2020; Published: 31 March 2020 Abstract: MicroRNAs (miRNAs) are small double-stranded RNAs that exert a fine-tuning sequence-specific regulation of cell transcriptome. While one unique miRNA regulates hundreds of mRNAs, each mRNA molecule is commonly regulated by various miRNAs that bind to complementary sequences at 3’-untranslated regions for triggering the mechanism of RNA interference. Unfortunately, dysregulated miRNAs play critical roles in many disorders, including Parkinson’s disease (PD), the second most prevalent neurodegenerative disease in the world. Treatment of this slowly, progressive, and yet incurable pathology challenges neurologists. In addition to L-DOPA that restores dopaminergic transmission and ameliorate motor signs (i.e., bradykinesia, rigidity, tremors), patients commonly receive medication for mood disorders and autonomic dysfunctions. -
Regulation of RNA Stability by Terminal Nucleotidyltransferases
Western University Scholarship@Western Electronic Thesis and Dissertation Repository 7-11-2019 10:30 AM Regulation of RNA stability by terminal nucleotidyltransferases Christina Z. Chung The University of Western Ontario Supervisor Heinemann, Ilka U. The University of Western Ontario Graduate Program in Biochemistry A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Christina Z. Chung 2019 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Biochemistry Commons Recommended Citation Chung, Christina Z., "Regulation of RNA stability by terminal nucleotidyltransferases" (2019). Electronic Thesis and Dissertation Repository. 6255. https://ir.lib.uwo.ca/etd/6255 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. Abstract The dysregulation of RNAs has global effects on all cellular pathways. The regulation of RNA metabolism is thus tightly controlled. Terminal RNA nucleotidyltransferases (TENTs) regulate RNA stability and activity through the addition of non-templated nucleotides to the 3′-end. TENT-catalyzed adenylation and uridylation have opposing effects; adenylation stabilizes while uridylation silences or degrades RNA. All TENT homologs were initially characterized as adenylyltransferases; the identification of caffeine-induced death suppressor protein 1 (Cid1) in Schizosaccharomyces pombe as an uridylyltransferase led to the reclassification of many TENTs as uridylyltransferases. Cid1 uridylates mRNAs that are subsequently degraded by the exonuclease Dis-like 3′-5′ exonuclease 2 (Dis3L2), while the human homolog germline-development 2 (Gld2) has been associated with adenylation of mRNAs and miRNAs and uridylation of Group II pre-miRNAs. -
Hydroxymethyl Cytidine As a Potential Inhibitor for Hepatitis C Virus
A Thesis entitled Synthesis of 2’- Hydroxymethyl Cytidine as a Potential Inhibitor for Hepatitis C Virus Polymerase Enzyme by Ali Hayder Hamzah Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry _________________________________________ Dr. Amanda C. Bryant-Friedrich, Committee Chair _________________________________________ Dr. Hermann Von Grafenstein, Committee Member _________________________________________ Dr. Caren L. Steinmiller, Committee Member _________________________________________ Dr. Amanda C. Bryant-Friedrich, Dean College of Graduate Studies The University of Toledo August 2016 Copyright 2016, Ali Hayder Hamzah This document is copyrighted material. Under copyright law, no parts of this document may be reproduced without the expressed permission of the author. An Abstract of Synthesis of 2’- Hydroxymethyl Cytidine as a Potential Inhibitor for Hepatitis C Virus Polymerase Enzyme by Ali Hayder Hamzah Submitted to the Graduate Faculty as partial fulfillment of the requirements for the Master of Science Degree in Medicinal Chemistry The University of Toledo August 2016 Hepatitis C virus infection (HCV) is a major cause of liver disease. Due to the asymptomatic nature of the infection, large populations are unware of their infection and become carriers, with progression to chronic stage including liver cirrhosis and hepatocellular carcinoma. Currently, there are seven genotypes and several subtypes of HCV; genotype 1 is the most global distributed form, acquired predominantly through illegal intravenous drug injection. HCV heterogeneity and high replication rates, lead to mutant formation and consequent reinfection. The diseases’ lack of susceptibility to antiviral agents facilitates chronic infection and as such is most challenging when searching for a cure. For decades, the standard of care (SOC) was a combination of PEGylated interferon-α (PEGINF-α) and ribavirin. -
New Hepatitis C Virus (HCV) Drugs and the Hope for a Cure: Concepts in Anti-HCV Drug Development
22 New Hepatitis C Virus (HCV) Drugs and the Hope for a Cure: Concepts in Anti-HCV Drug Development Jean-Michel Pawlotsky, MD, PhD1,2 1 National Reference Center for Viral Hepatitis B, C and D, Department Address for correspondence Jean-Michel Pawlotsky, MD, PhD, of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, Department of Virology, Hôpital Henri Mondor, 51 avenue du Maréchal France de Lattre de Tassigny, 94010 Créteil, France 2 INSERM U955, Créteil, France (e-mail: [email protected]). Semin Liver Dis 2014;34:22–29. Abstract The development of new models and tools has led to the discovery and clinical development of a large number of new anti-hepatitis C virus (HCV) drugs, including direct-acting antivirals and host-targeted agents. Surprisingly, curing HCV infection appears to be easy with these new drugs, provided that a potent drug combination with a high barrier to resistance is used. HCV infection cure rates can be optimized by combining drugs with synergistic antiviral effects, tailoring treatment duration to the patients’ needs, and/or using ribavirin. Two HCV drugs have been approved in 2011— Keywords telaprevir and boceprevir, both first-wave, first-generation NS3-4A protease inhibitors, ► hepatitis C virus two others in 2013/2014—simeprevir, a second-wave, first-generation NS3-4A protease ► direct-acting inhibitor, and sofosbuvir, a nucleotide analogue inhibitor of the viral polymerase. antivirals Numerous other drugs have reached phase II or III clinical development. From 2015 ► host-targeted agents and onwards, interferon-containing regimens will disappear, replaced by interferon-free ► simeprevir regimens yielding infection cure rates over 90%. -
Microrna Maturation -- Methods and Protocols
Methods in Molecular Biology 1095 Christoph Arenz Editor miRNA Maturation Methods and Protocols www.ketabdownload.com M ETHODS IN MOLECULAR BIOLOGY™ Series Editor John M. Walker School of Life Sciences University of Hertfordshire Hat fi eld, Hertfordshire, AL10 9AB, UK For further volumes: http://www.springer.com/series/7651 www.ketabdownload.com www.ketabdownload.com miRNA Maturation Methods and Protocols Edited by Christoph Arenz Institute for Chemistry, Humboldt-Universität zu Berlin, Berlin, Germany www.ketabdownload.com Editor Christoph Arenz Institute for Chemistry Humboldt-Universität zu Berlin Berlin, Germany ISSN 1064-3745 ISSN 1940-6029 (electronic) ISBN 978-1-62703-702-0 ISBN 978-1-62703-703-7 (eBook) DOI 10.1007/978-1-62703-703-7 Springer New York Heidelberg Dordrecht London Library of Congress Control Number: 2013949785 © Springer Science+Business Media New York 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifi cally the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfi lms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifi cally for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher’s location, in its current version, and permission for use must always be obtained from Springer. -
Noncoding RNA Therapeutics — Challenges and Potential Solutions
PERSPECTIVES siRNAs or ASOs that influence only a single target gene. Noncoding RNA therapeutics — The diverse functional repertoire of lncRNAs reveals various opportunities for challenges and potential solutions their therapeutic targeting, the means of which need to be adjusted to the mode of Melanie Winkle, Sherien M. El-Daly, Muller Fabbri and George A. Calin action of the lncRNA. LncRNA targeting may include transcriptional inhibition, Abstract | Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs post-transcriptional inhibition, steric (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach hindrance of secondary structure formation for the treatment of cancers, as well as many other diseases. Over the past decade, or protein interactions, introduction of substantial effort has been made towards the clinical application of RNA-based synthetic (for example, circular) lncRNAs, and modulation of lncRNA genomic loci or therapeutics, employing mostly antisense oligonucleotides and small interfering expression patterns via CRISPR–Cas9 and RNAs, with several gaining FDA approval. However, trial results have so far been CRISPR–Cas13, respectively (reviewed in ambivalent, with some studies reporting potent effects whereas others REF.17). An interesting development is the demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs exploration of natural antisense transcripts are undergoing clinical testing, and lncRNA-based therapeutics are gaining (NATs): lncRNAs that are transcribed in interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics the antisense direction to coding genes, and negatively regulate them in cis. ASOs — including issues associated with specificity, delivery and tolerability — and focus that target NATs, termed ‘antagoNATs’ on promising emerging approaches that aim to boost their success. -
Discovering the First Microrna-Targeted Drug
Published October 29, 2012 JCB: Feature Discovering the first microRNA-targeted drug Morten Lindow1,2 and Sakari Kauppinen2,3 1Department of Biology, The Bioinformatics Centre, University of Copenhagen, DK-2200 Copenhagen, Denmark 2Santaris Pharma, DK-2970 Hørsholm, Denmark 3Department of Health Science and Technology, Aalborg University Copenhagen, DK-2450 Copenhagen SV, Denmark MicroRNAs (miRNAs) are important post-transcriptional first human oncogenic miRNAs (Eis et al., 2005; He et al., 2005; regulators of nearly every biological process in the cell Costinean et al., 2006). Since then, 18,226 miRNAs have been an- notated in animals, plants, and viruses, including 1,921 miRNAs and play key roles in the pathogenesis of human disease. encoded in the human genome (Kozomara and Griffiths-Jones, As a result, there are many drug discovery programs 2011). Indeed, miRNAs are predicted to repress a large fraction that focus on developing miRNA-based therapeutics. The of all protein-coding genes and to participate in the regulation most advanced of these programs targets the liver- of almost every biological process in the cell (Kloosterman and Downloaded from expressed miRNA-122 using the locked nucleic acid Plasterk, 2006; Bushati and Cohen, 2007; Bartel, 2009; Friedman (LNA)–modified antisense oligonucleotide miravirsen. et al., 2009; Ambros, 2011). Moreover, recent work implies that miRNA dysregulation is frequently associated with the patho- Here, we describe the discovery of miravirsen, which is genesis of human diseases (Gottwein and Cullen, 2008; Ventura currently in phase 2 clinical trials for treatment of hepatitis and Jacks, 2009; Williams et al., 2009; Mendell and Olson, C virus (HCV) infection. -
The Epigenetic Implication in Coronavirus Infection and Therapy
Atlante et al. Clin Epigenet (2020) 12:156 https://doi.org/10.1186/s13148-020-00946-x REVIEW Open Access The epigenetic implication in coronavirus infection and therapy Sandra Atlante1, Alessia Mongelli1, Veronica Barbi1, Fabio Martelli2, Antonella Farsetti3* and Carlo Gaetano1* Abstract Epigenetics is a relatively new feld of science that studies the genetic and non-genetic aspects related to heritable phenotypic changes, frequently caused by environmental and metabolic factors. In the host, the epigenetic machin- ery can regulate gene expression through a series of reversible epigenetic modifcations, such as histone methylation and acetylation, DNA/RNA methylation, chromatin remodeling, and non-coding RNAs. The coronavirus disease 19 (COVID-19) is a highly transmittable and pathogenic viral infection. The Severe Acute Respiratory Syndrome Coro- navirus 2 (SARS-CoV-2), which emerged in Wuhan, China, and spread worldwide, causes it. COVID-19 severity and consequences largely depend on patient age and health status. In this review, we will summarize and comparatively analyze how viruses regulate the host epigenome. Mainly, we will be focusing on highly pathogenic respiratory RNA virus infections such as coronaviruses. In this context, epigenetic alterations might play an essential role in the onset of coronavirus disease complications. Although many therapeutic approaches are under study, more research is urgently needed to identify efective vaccine or safer chemotherapeutic drugs, including epigenetic drugs, to cope with this viral outbreak and to develop pre- and post-exposure prophylaxis against COVID-19. Keywords: Coronaviruses, Epigenetics, Nucleic acids, Aging, Metabolism, Chronic disease Introduction Te name SARS-CoV-2 was assigned since its RNA virus Te severe acute respiratory syndrome coronavirus 2 genome is closely related to the severe acute respiratory (SARS‐CoV‐2) is a severe new disease that emerged in syndrome (SARS)-CoV, which emerged in human spe- Wuhan, China, in December 2019 [1]. -
Complete 3D Description of Dynamic Behaviour of Enzyme Mimics: Role of Various Structural Elements in Catalysis and Interactions with Bio-Target
Complete 3D description of dynamic behaviour of enzyme mimics: role of various structural elements in catalysis and interactions with bio-target A thesis submitted to the University of Manchester for the degree of Doctor in Philosophy in the Faculty of Biology, Medicine and Health 2018 Linda T. Trivoluzzi The University of Manchester School of Health Sciences Division of Pharmacy and Optometry Table of Contents List of Figures……………………………………………………………………………..….……. 7 List of Tables……………………………………………………………………………………..... 20 List of Schemes……………………………………………………..…………………….….…….. 21 List of abbreviations……………………………………………………………………….…….… 22 Abstract………………………………………………………………………………….….……… 25 Declaration……………………………………………………………………….……….…..……. 26 Copyright Statement……………………………………………………………….….………....… 27 Acknowledgements…………………………………………………………………….………..…. 28 Publications…………………………………………………………………………………………. 29 Chapter 1: Introduction 1.1 Low molecular weight drugs: decline in drug discovery process………………… 30 1.2 RNA targeting………………………………………………………………………..……… 33 1.2.1 Rationale, possible impact and advantages of RNA targeting………………………..…… 33 1.2.2 MicroRNAs as attractive therapeutic targets……………………………………………… 37 1.3 Spontaneous, enzymatic and chemical catalysis of RNA cleavage…………..….. 38 1.3.1 RNA chemical stability……………………………………………………………………. 38 1.3.2 Spontaneous RNA transesterification……………………………………………………… 39 1.3.3 Base catalysis……………………………………………………………………………… 40 1.3.4 Metal ion catalysis……………………………………………………………………….… 41 1.3.5 RNA cleaving enzymes…………………………………………………………………….