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Author: Austin Yu Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Drug discovery in the last century has largely been dominated by therapeutics targeting proteins. RNA targeting has remained largely elusive and high-risk, but some recent therapeutics have seen great utility and success. One area where RNA targeting has strong potential is in tackling viral infections. Many viruses, especially RNA viruses have high rates of mutation that sometimes confer treatment resistance. A method to counter the high mutation rates of viruses is to develop treatments which target conserved regions of the viral genome that are highly structured. For my studies, two structured RNA targets were probed: the Zika virus (ZIKV) stem loop A (SLA) and the SARS-CoV-2 RNA pseudoknot. Replication of mosquito-borne pathogenic flaviviruses like Zika virus depends on a noncoding RNA motif in the 5' untranslated region of the genome which recruits the viral NS5 replicase. The three-dimensional architecture of the replication promoter RNA is termed the SLA. Sequence alignment as well as conservation and covariation analyses as evidence support a canonical RNA three-way junction (3WJ) architecture for the SLA RNA. The SLA 3WJ also influences viral translation by interaction with the E protein coding region and the conformational flexibility of the SLA 3WJ may be exploited to discover selectively binding ligands that interfere with viral replication. As a proof of concept, antisense DNA ligands hybridized at a domain of the SLA RNA served as surrogate ligands eliciting an extensive conformational change in the 3WJ fold which is readily detected by measuring FRET response. The FRET binding assay provides a useful tool for the discovery of small molecule ligands that target the flavivirus replication promoter. Another FRET binding assay was utilized to discover ligands which selectively bind the SARS-CoV-2 RNA pseudoknot. The discovered ligands consisted of aminoglycosides such as tobramycin and were retested with a phenotypic in vitro translation assay to assess for physiological relevance. While the results were not physiologically relevant, the discovered ligands act as a foundation for future work for discovering pan-SARS-CoV-2 mutant treatments and highlight the potential in targeting structured RNA as a drug target.
Author: Austin Yu Publisher: ISBN: Category : Languages : en Pages : 0
Book Description
Drug discovery in the last century has largely been dominated by therapeutics targeting proteins. RNA targeting has remained largely elusive and high-risk, but some recent therapeutics have seen great utility and success. One area where RNA targeting has strong potential is in tackling viral infections. Many viruses, especially RNA viruses have high rates of mutation that sometimes confer treatment resistance. A method to counter the high mutation rates of viruses is to develop treatments which target conserved regions of the viral genome that are highly structured. For my studies, two structured RNA targets were probed: the Zika virus (ZIKV) stem loop A (SLA) and the SARS-CoV-2 RNA pseudoknot. Replication of mosquito-borne pathogenic flaviviruses like Zika virus depends on a noncoding RNA motif in the 5' untranslated region of the genome which recruits the viral NS5 replicase. The three-dimensional architecture of the replication promoter RNA is termed the SLA. Sequence alignment as well as conservation and covariation analyses as evidence support a canonical RNA three-way junction (3WJ) architecture for the SLA RNA. The SLA 3WJ also influences viral translation by interaction with the E protein coding region and the conformational flexibility of the SLA 3WJ may be exploited to discover selectively binding ligands that interfere with viral replication. As a proof of concept, antisense DNA ligands hybridized at a domain of the SLA RNA served as surrogate ligands eliciting an extensive conformational change in the 3WJ fold which is readily detected by measuring FRET response. The FRET binding assay provides a useful tool for the discovery of small molecule ligands that target the flavivirus replication promoter. Another FRET binding assay was utilized to discover ligands which selectively bind the SARS-CoV-2 RNA pseudoknot. The discovered ligands consisted of aminoglycosides such as tobramycin and were retested with a phenotypic in vitro translation assay to assess for physiological relevance. While the results were not physiologically relevant, the discovered ligands act as a foundation for future work for discovering pan-SARS-CoV-2 mutant treatments and highlight the potential in targeting structured RNA as a drug target.
Author: John Schneekloth Publisher: John Wiley & Sons ISBN: 3527351000 Category : Medical Languages : en Pages : 418
Book Description
Discover a new paradigm in drug discovery that greatly expands the space of addressable drug targets and potential novel drugs Existing paradigms for drug discovery have focused largely on enzymes and other proteins as drug targets. In recent years, however, different varieties of ribonucleic acids have emerged as a viable focus for target-based drug discovery, with the potential to revolutionize the strategy and approach for this essential step in the drug development process. RNA as a Drug Target: The Next Frontier for Medicinal Chemistry offers a practice-oriented introduction to developing drug-like small molecules that selectively modulate both coding and non-coding RNAs. Beginning with a description and characterization of existing druggable RNAs, the book discusses how to approach different RNA targets for drug discovery. The result is a crucial resource for targeting RNAs and creating the next generation of life-saving pharmaceuticals. RNA as a Drug Target readers will also find: A complete “toolbox” for working with RNA, from structure determination to screening and lead generation techniques A wide range of addressable targets and mechanisms, including splicing modulation, riboswitches, targeted degradation, and more Authoritative discussion of the potential of RNA-targeted small molecule therapeutics for drugging the epitranscriptome RNA as a Drug Target provides an expert introduction to a new frontier in pharmaceutical research for medicinal chemists, biochemists, molecular biologists, and members of the pharmaceutical industry.
Author: Rachel J. Hagey Publisher: ISBN: Category : Languages : en Pages :
Book Description
RNA viruses cause a variety of acute and chronic diseases in humans. In addition to encoding for viral proteins, the genomes of RNA viruses often harbor secondary and tertiary RNA structures that have been associated with functions essential for successful virus replication and propagation. While antiviral research has focused almost exclusively on targeting viral proteins, the importance of RNA structural elements in virus lifecycles suggest these motifs could be promising therapeutic targets. In this thesis, I will dissect the contributions and druggability of RNA structures and complexes in two distinct phases of the viral lifecycle: first, in the virus packaging and production of influenza A virus (IAV), a negative-strand segmented RNA virus responsible for severe, sometimes fatal respiratory disease with pandemic potential; and second, in the replication complex of hepatitis C virus (HCV), a positive-strand RNA virus associated with chronic liver disease and cancer. To characterize the role of RNA secondary structures in IAV virus packaging, I employed the chemical mapping technique, Selective 2′ Hydroxyl Acylation analyzed by Primer Extension (SHAPE), which uses experimental probing data to guide computational modeling of high resolution RNA structure. This method enabled me to determine the RNA secondary structure of the IAV 5′ packaging signal region of virus genome segment PB2, the structures of known mutations in PB2 that disrupt virus packaging, as well as the discovery and characterization of novel mutants. Cutting-edge multidimensional mapping methods, Mutate-and-Map and Mutate-Map-Rescue, built upon this technical base and provided structural validation through discovery of compensatory mutant partners, which later informed both the in vivo exploration of packaging-defective viruses, as well as the design of locked nucleic acids (LNAs) targeting this structure. In vitro and in vivo drug targeting by LNAs of this IAV packaging signal structure exhibited powerful prophylactic and therapeutic efficacy. Combined, this work points to the promise of RNA secondary structures as valid antiviral targets, and sheds new light on IAV genome packaging mechanisms. The second section of my thesis built upon previous research in the lab. SHAPE was again employed to map both the RNA secondary structure of the HCV 5′ internal ribosomal entry site (IRES) and the structural interaction between the virus's 5′ untranslated region (UTR) and the miR-122 complex found to mediate viral replication. As an extension of this investigation, we sought to better parse the interaction of the viral replication complex with the host membrane in real-time. To do so, we employed a supported lipid-bilayer (SLB) platform and coupled it with quartz crystal microbalance with dissipation (QCM-D) to reconstitute and explore how components of the HCV replicase complex affect viral RNA replication and in vitro RNA transcription. The core enzyme of this complex, the NS5B RNA-dependent RNA polymerase, is required for in vivo virus replication and is a prime drug target for current and future HCV antiviral therapies. The reconstitution of full length NS5B in a membranous environment capable of active polymerase function, however, had not been demonstrated. Here, the SLB/QCM-D platform made it possible to reconstruct an in silico biological mimic of the host membrane to quantitatively probe and observe interactions between the membrane, the HCV viral RNA template and its associated viral proteins in real time. Together, these provide strong proof-of-concept for use of this technique in further understanding of the molecular details of HCV genome replication and future drug screening applications.
Author: Amanda L. Garner Publisher: Springer ISBN: 3319680919 Category : Science Languages : en Pages : 263
Book Description
Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors.
Author: M.R.S. Rao Publisher: Springer ISBN: 9811052034 Category : Medical Languages : en Pages : 336
Book Description
This contributed volume offers a comprehensive and detailed overview of the various aspects of long non-coding RNAs and discusses their emerging significance. Written by leading experts in the field, it motivates young researchers around the globe, and offers graduate and postgraduate students fascinating insights into genes and their regulation in eukaryotes and higher organisms.
Author: Satya Prakash Gupta Publisher: Academic Press ISBN: 0128154233 Category : Science Languages : en Pages : 496
Book Description
Viral Polymerases: Structures, Functions and Roles as Antiviral Drug Targets presents in-depth study information on the structure and functions of polymerases and their roles in the lifecycle of viruses, and as drug targets. Viral polymerases constitute a vital component in the lifecycle of many viruses, such as human immunodeficiency virus (HIV), hepatitis viruses, influenza virus, and several others. They are essentially required for the replication of viruses. Thus, the polymerases that can be found in viruses (called viral polymerases) represent favorable targets for the design and development of antiviral drugs. Provides comprehensive, state-of-the-art coverage on virus infections, the virus lifecycle, and mechanisms of polymerase inhibition Analyzes the structure-activity relationships of inhibitors of each viral polymerase Presents a consistent and comprehensive coverage of all aspects of viral polymerases, including structure, function and their role as antiviral drug targets
Author: Dagmar Klostermeier Publisher: Walter de Gruyter ISBN: 3110284952 Category : Science Languages : en Pages : 432
Book Description
While structure-function relationships of proteins have been studied for a long time, structural studies of RNA face additional challenges. Nevertheless, with the continuous discovery of novel RNA molecules with key cellular functions and of novel pathways and interaction networks, the need for structural information of RNA is still increasing. This volume provides an introduction into techniques to assess structure and folding of RNA. Each chapter explains the theoretical background of one technique, and illustrates possibilities and limitations in selected application examples.
Author: Mauricio G. Mateu Publisher: Springer Science & Business Media ISBN: 9400765525 Category : Medical Languages : en Pages : 734
Book Description
This book contemplates the structure, dynamics and physics of virus particles: From the moment they come into existence by self-assembly from viral components produced in the infected cell, through their extracellular stage, until they recognise and infect a new host cell and cease to exist by losing their physical integrity to start a new infectious cycle. (Bio)physical techniques used to study the structure of virus particles and components, and some applications of structure-based studies of viruses are also contemplated. This book is aimed first at M.Sc. students, Ph.D. students and postdoctoral researchers with a university degree in biology, chemistry, physics or related scientific disciplines who share an interest or are actually working on viruses. We have aimed also at providing an updated account of many important concepts, techniques, studies and applications in structural and physical virology for established scientists working on viruses, irrespective of their physical, chemical or biological background and their field of expertise. We have not attempted to provide a collection of for-experts-only reviews focused mainly on the latest research in specific topics; we have not generally assumed that the reader knows all of the jargon and all but the most recent and advanced results in each topic dealt with in this book. In short, we have attempted to write a book basic enough to be useful to M.Sc and Ph.D. students, as well as advanced and current enough to be useful to senior scientists with an interest in Structural and/or Physical Virology.
Author: Akio Adachi Publisher: Frontiers Media SA ISBN: 2889190242 Category : Languages : en Pages : 104
Book Description
Viruses are absolutely and strictly dependent on target host cells for their replication. However, they have their own unique strategies at each replication step from the entry into cells, transcription, translation, assembly of viral genome/proteins, and up to the release of progeny virions from cells. We virologists have to understand these complex biological interactions between viruses and host cells. Importantly, extensive studies based on bio-structural technology have revealed in succession the detailed and bottom line mechanisms of viral replication processes otherwise impossible. We now know the highly dynamic nature of viral genome/proteins, and are impressed by their ingeniously organized functionality in hostile host environments. For characterization of viruses as a unique genetic entity and pathogenic agent, it has been critical to investigate thoroughly the individual viral components and host factors involved in the virus replication cycle. Because many viral and cellular factors essential for viral replication and pathogenicity have been newly discovered through the efforts of virologists, the necessity of contribution to the progress of virology by the structural biology is now greatly increasing. To fully understand precise mechanisms underlying the functional interaction of viral and host molecules, needless to say, it is crucially required to have their structural information. We need to know molecular details of the nucleic acids, proteins, and interacting molecules. The information indispensable for understanding certain biological phenomena may only be provided by high-resolution three-dimensional structures. Of note, a number of anti-viral drugs have been generated based on the structural information. The interacting interfaces between virus and host components, which are important for viral replication, can be potent targets for anti-viral drugs. Their structural characterization would lead to designing rigid anti-viral drugs and/or vaccines. In this Research Topic, we wish to summarize and review what the structural biology has accomplished so far to resolve the important virological issues. We also wish to describe the perspective of the structural biology for the future virology. Finally, the presentation of ongoing original works is greatly encouraged.
Author: Austin Yu
Author: Austin Yu
Author: John Schneekloth
Author: Rachel J. Hagey
Author: Amanda L. Garner
Author: M.R.S. Rao
Author: Satya Prakash Gupta
Author: Steven T. Runyon
Author: Dagmar Klostermeier
Author: Mauricio G. Mateu
Author: Akio Adachi