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Author: Md Ismail Hossain Publisher: ISBN: Category : Drug development Languages : en Pages : 0
Book Description
Antibiotic resistance is a global threat beside the ongoing pandemic by SARS-CoV-2. The number of deaths due to antibiotic-resistant infections is increasing at an alarming rate. The COVID-19 pandemic has already claimed millions of deaths worldwide. Fighting against antibiotic-resistant superbugs and the SARS-CoV-2 has become a challenge. A significant amount of research is going on to develop the vaccine and small molecule antiviral and antibacterial therapeutics targeting proteins. Fortunately, novel non-coding regulatory RNA targets have been identified for developing new antibacterial and antiviral drugs such as bacterial T-box riboswitch, RNA thermometers, and viral stem-loop II motif. T-box riboswitch can control the transcription or translation of amino acid-related genes in bacteria by forming unique interactions between tRNA and mRNA. RNA thermometers (RNATs) are temperature-responsive riboswitches that control the translation based on temperature sensing thus controlling the interaction with the mRNA and 16S rRNA. In Shigella dysenteriae, three RNATs, i.e., ompA, shuT, and shuA, have been discovered. ompA RNAT controls the translation of outer membrane protein A. shuT, and shuA RNAT controls the translation of two proteins that are crucial to the bacterial heme utilization system. The Stem-loop II motif (S2M) is a highly conserved RNA element found in most coronaviruses, astroviruses, and picornaviruses that plays a potential role in viral replication and invasion. The RNA structure plays a significant role in its regulatory function for all of these potential therapeutic targets. Consequently, it is essential to examine the factors that affect the RNA structure and RNA-RNA interaction. Despite having limited building blocks, RNA has diverse functions in the cells. Base protonation and protonated base pairs often occur in RNA when interacting with other biomolecules, thus could play a critical role in vital biological processes. Different biophysical assays, including UV use in monitoring thermal denaturation, FRET, fluorescence polarization, chemical and enzymatic probing, EMSA, and In vitro transcription assay were used to probe the RNA structures, stability, conformation, and potential function.
Author: Md Ismail Hossain Publisher: ISBN: Category : Drug development Languages : en Pages : 0
Book Description
Antibiotic resistance is a global threat beside the ongoing pandemic by SARS-CoV-2. The number of deaths due to antibiotic-resistant infections is increasing at an alarming rate. The COVID-19 pandemic has already claimed millions of deaths worldwide. Fighting against antibiotic-resistant superbugs and the SARS-CoV-2 has become a challenge. A significant amount of research is going on to develop the vaccine and small molecule antiviral and antibacterial therapeutics targeting proteins. Fortunately, novel non-coding regulatory RNA targets have been identified for developing new antibacterial and antiviral drugs such as bacterial T-box riboswitch, RNA thermometers, and viral stem-loop II motif. T-box riboswitch can control the transcription or translation of amino acid-related genes in bacteria by forming unique interactions between tRNA and mRNA. RNA thermometers (RNATs) are temperature-responsive riboswitches that control the translation based on temperature sensing thus controlling the interaction with the mRNA and 16S rRNA. In Shigella dysenteriae, three RNATs, i.e., ompA, shuT, and shuA, have been discovered. ompA RNAT controls the translation of outer membrane protein A. shuT, and shuA RNAT controls the translation of two proteins that are crucial to the bacterial heme utilization system. The Stem-loop II motif (S2M) is a highly conserved RNA element found in most coronaviruses, astroviruses, and picornaviruses that plays a potential role in viral replication and invasion. The RNA structure plays a significant role in its regulatory function for all of these potential therapeutic targets. Consequently, it is essential to examine the factors that affect the RNA structure and RNA-RNA interaction. Despite having limited building blocks, RNA has diverse functions in the cells. Base protonation and protonated base pairs often occur in RNA when interacting with other biomolecules, thus could play a critical role in vital biological processes. Different biophysical assays, including UV use in monitoring thermal denaturation, FRET, fluorescence polarization, chemical and enzymatic probing, EMSA, and In vitro transcription assay were used to probe the RNA structures, stability, conformation, and potential function.
Author: Ali Hamed Aldhumani Publisher: ISBN: Category : Antibacterial agents Languages : en Pages : 275
Book Description
The T-box riboswitch is a cis-acting regulator RNA element found primarily in the 5′ untranslated region of Gram-positive bacterial mRNAs that code for aminoacyl synthetases and other amino acid-related genes. Many of these genes are essential to the survival of the respective bacteria. The T-box riboswitch functions as a two-part system containing an aptamer domain and expression platform that together regulate transcription or translation. A gene-specific uncharged tRNA functions as the effector ligand by binding in the aptamer domain resulting in transcription readthrough (or translation initiation). The presence of the T-box riboswitch only in bacterial and not mammalian cells makes it an interesting drug target, however targeting specific RNA constructs remains a major challenge. Identifying small molecules that can bind discriminately to specific RNA secondary and tertiary structures requires strategically designed prediction models. In this study, combinatory compound screening using molecular modeling and moderate throughput assays was used to identify `hit' compounds that could be studied further with the potential to design ideal small molecule inhibitors. The potential role of T-box riboswitch agonists like polyamines, which are ubiquitous in binding to nucleic acids, to mimic in vivo conditions in vitro was investigated to help identify compounds of interest early in the screening process. Using optimized primary screening assays, a natural products library, RNA-targeted synthetic compounds, and computational methods (e.g., docking, molecular dynamics); a strategy for developing a pharmacophore model for the T-box riboswitch was established. The combinatory screening approach developed could be used for other structured RNA targets of interest. A pharmacophore workflow was designed with iterative improvements assisted by molecular dynamic simulations to obtain a validated pharmacophore model. The molecular dynamic simulations were initially optimized using the SARS-CoV-2 stem-loop II motif RNA and then applied to the T-box riboswitch antiterminator RNA.
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: 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: Richard S. Larson Publisher: ISBN: 9781617799655 Category : Bioinformatics Languages : en Pages : 374
Book Description
Recent advances in drug discovery have been rapid. The second edition of Bioinformatics and Drug Discovery has been completely updated to include topics that range from new technologies in target identification, genomic analysis, cheminformatics, protein analysis, and network or pathway analysis. Each chapter provides an extended introduction that describes the theory and application of the technology. In the second part of each chapter, detailed procedures related to the use of these technologies and software have been incorporated. Written in the highly successful Methods in Molecular Biology series format, the chapters include the kind of detailed description and implementation advice that is crucial for getting optimal results in the laboratory. Thorough and intuitive, Bioinformatics and Drug Discovery, Second Edition seeks to aid scientists in the further study of the rapidly expanding field of drug discovery.
Author: Xinyong Liu Publisher: Springer Nature ISBN: 9811602670 Category : Medical Languages : en Pages : 357
Book Description
This book summarizes state-of-the-art antiviral drug design and discovery approaches starting from natural products to de novo design, and provides a timely update on recently approved antiviral drugs and compounds in advanced clinical development. Special attention is paid to viral infections with a high impact on the world population or highly relevant from the public health perspective (HIV, hepatitis C, influenza virus, etc.). In these chapters, limitations associated with adverse effects and emergence of drug resistance are discussed in detail. In addition to classical antiviral strategies, chapters will be dedicated to discuss the non-classical drug development strategies to block viral infection, for instance, allosteric inhibitors, covalent antiviral agents, or antiviral compounds targeting protein–protein interactions. Finally, current prospects for producing broad-spectrum antiviral inhibitors will be also addressed. The book is distinctive in providing the most recent update in the rapidly evolving field of antiviral therapeutics. Authoritative reviews are written by international scientists well known for their contributions in their topics of research, which makes this book suitable for researchers not only within the antiviral research community but also attractive to a broad audience in the drug discovery field. This book covers molecular structures and biochemical mechanisms mediating the antiviral effects, while discussing various ligand design strategies, which include traditional medicinal chemistry, computational chemistry, and chemical biology approaches. The book provides a comprehensive review of antiviral drug discovery and development approaches, particularly focusing on current innovations and future trends.
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: Md Ismail Hossain
Author: Md Ismail Hossain
Author: Ali Hamed Aldhumani
Author: John Schneekloth
Author: Austin Yu
Author: Richard S. Larson
Author: Mahesh Uttamchandani
Author: Xinyong Liu
Author: M.R.S. Rao
Author: Roger N. Rosenberg
Author: Bruce Alberts