RNA As a Drug Target : The Next Frontier for Medicinal Chemistry

• Autore: Schneekloth John
• Pubblicazione: Newark : , : John Wiley & Sons, Incorporated, , 2024; ©2024
• Edizione: 1st ed.
• Descrizione fisica: 1 online resource (411 pages)
• Altri autori: PetterssonMartin MannholdRaimund BuschmannHelmut HolenzJörg
• Nota di contenuto: Cover -- Title Page -- Copyright -- Contents -- Series Editors' Preface -- Preface -- Chapter 1 Introduction -- References -- Chapter 2 RNA Structure Probing, Dynamics, and Folding -- 2.1 Introduction -- 2.1.1 Relevance of RNA Structure in Disease -- 2.1.2 Challenges in Studying RNA Structures -- 2.2 Experimentally Guided RNA Structure Modeling -- 2.2.1 Structural Interrogation of RNA Nucleotides via Chemical Probing -- 2.2.1.1 Limits of RNA Chemical Probing -- 2.2.2 Direct Mapping of RNA-RNA Interactions -- 2.2.2.1 Limits of RNA-RNA Interaction Mapping -- 2.2.3 Mapping Spatially Proximal Nucleotides in RNA molecules -- 2.2.3.1 Limits of Methods for Spatial Proximity Mapping -- 2.3 Dealing with RNA Structure Heterogeneity -- 2.4 Querying RNA-Small Molecule Interactions with Chemical Probing -- 2.5 Conclusions and Future Prospects -- References -- Chapter 3 High‐Resolution Structures of RNA -- 3.1 Introduction -- 3.2 X‐Ray Crystallography -- 3.3 NMR Spectroscopy -- 3.4 Cryo‐EM -- 3.5 3D Structure Prediction and Integrative Approaches -- 3.6 Conclusions -- Acknowledgments -- Conflicts of Interest -- References -- Chapter 4 Screening and Lead Generation Techniques for RNA Binders -- 4.1 Knowledge‐Based Versus Agnostic Screening -- 4.2 Virtual Screening -- 4.3 Screening Methods -- 4.3.1 High‐Throughput Screening (HTS) -- 4.3.1.1 Mass Spectrometry -- 4.3.1.2 HTS of RNA Using Direct MS Approaches -- 4.3.1.3 HTS of RNA Using Indirect MS Approaches -- 4.3.1.4 DNA‐Encoded Libraries (DELs) -- 4.3.1.5 Microarray Screening -- 4.3.1.6 Fragment‐Based Drug Discovery -- 4.3.1.7 Phage Display -- 4.3.2 Orthogonal Methods -- 4.3.2.1 Surface Plasmon Resonance -- 4.3.2.2 Fluorescence‐Based Assays -- 4.3.2.3 Microscale Thermophoresis (MST) -- 4.3.2.4 Isothermal Titration Calorimetry (ITC) -- 4.4 Binding Site Identification/Target Engagement -- 4.4.1 Covalent Methods. ; 4.4.2 Competition with an Antisense Oligonucleotide (ASO) -- 4.5 Defining SAR and Functional Assays -- 4.5.1 Functional Assays -- 4.5.2 Phenotypic Screens -- 4.6 Identifying a Lead Series -- 4.6.1 Hit Optimization -- 4.6.2 Risdiplam Hit‐to‐Lead -- 4.6.3 Branaplam Lead Generation -- 4.6.4 Zotatifin Lead Generation -- 4.7 Concluding Thoughts and Outlook -- Acknowledgments -- References -- Chapter 5 Chemical Matter That Binds RNA -- 5.1 Introduction -- 5.2 Natural Ligands -- 5.2.1 Aminoglycosides -- 5.2.2 Tetracyclines -- 5.2.3 Macrolides -- 5.2.4 Native Riboswitch Ligands -- 5.3 Commercial Ligands -- 5.3.1 Industrial Libraries -- 5.3.2 Academic Libraries -- 5.4 Synthetic Ligands -- 5.4.1 Benzimidazoles and Purines -- 5.4.2 Naphthalenes, Quinolines, and Quinazolines -- 5.4.3 Oxazolidinones -- 5.4.4 Amilorides -- 5.4.5 Diphenyl Furan -- 5.4.6 Multivalent Ligands -- 5.5 Computational Tools for the Exploration of Chemical Space -- 5.5.1 Similarity Searches and Principal Component Analysis -- 5.5.2 Additional Machine‐Learning Tools -- 5.5.3 Structure‐Based Ligand Design -- 5.6 Case Studies in Examining and Expanding RNA‐Targeted Chemical Space -- 5.6.1 Using QSAR to Probe RNA‐Targeting Small‐Molecule Properties -- 5.6.2 Evaluating the Chemical Space of Natural, Synthetic, and Commercial Ligands -- 5.7 Conclusions and Outlook -- Acknowledgments -- References -- Chapter 6 MicroRNAs as Targets for Small‐Molecule Binders -- 6.1 Introduction -- 6.2 MicroRNAs -- 6.3 MicroRNAs Biogenesis -- 6.4 Targeting MicroRNAs with Small‐Molecule RNA Binders -- 6.4.1 Induction of miRNAs Expression: Tackling the Decrease of Tumor Suppressor miRNAs -- 6.4.2 Inhibition of miRNAs Production: Pre‐ and Pri‐miRNA Binders -- 6.4.2.1 Discovery of miRNAs Inhibitors by Intracellular Assays -- 6.4.2.2 Target‐Based In Vitro Assays. ; 6.4.2.3 Design of Specific Ligands of Pre‐ and Pri‐miRNAs -- 6.4.2.4 Fragment‐Based Drug Design -- 6.4.2.5 DNA‐Encoded Libraries (DELs) -- 6.5 Inhibition of RNA-Protein Interactions in miRNAs Pathways -- 6.6 Adding Cleavage Properties to miRNAs Interfering Agents -- 6.7 Conclusions -- References -- Chapter 7 Pre‐mRNA Splicing Modulation -- 7.1 Introduction -- 7.2 Overview of Splicing Biology -- 7.2.1 The Spliceosome -- 7.2.2 Classes of Alternative Splicing -- 7.3 Pharmacological Mechanisms of Splicing Modulation -- 7.3.1 Cis‐ and Trans‐Regulatory Elements (Splicing Factors) -- 7.3.1.1 Stabilization of Cis‐Regulatory Elements -- 7.3.1.2 Destabilization of Cis‐Regulatory Elements -- 7.3.1.3 Inhibition of Cis‐Regulatory RNA-Protein Interactions -- 7.3.1.4 Inhibition of Trans‐Regulatory Elements -- 7.3.1.5 Degradation of Trans‐Regulatory Elements -- 7.3.1.6 Inhibition of Trans‐Regulatory Element Protein-Protein Interactions (PPIs) -- 7.3.1.7 Stabilization of Trans‐Regulatory Element RNA-Protein Interactions (RPIs) -- 7.3.2 Kinases and Phosphatases -- 7.3.2.1 Challenges in Targeting Kinases -- 7.3.2.2 Inhibition of Kinases -- 7.3.2.3 Activation and Degradation of Kinases -- 7.3.2.4 Inhibition and Activation of Protein Phosphatases -- 7.3.3 Epigenetic Writers and Erasers -- 7.3.3.1 Inhibition of Epigenetic Writers -- 7.3.4 RNA Helicases -- 7.3.5 Drugging the Spliceosome -- 7.3.5.1 Inhibition of U2 snRNP Recognition of the 3′‐Splice Site -- 7.3.5.2 E7107 -- 7.3.5.3 H3B‐8800 -- 7.3.5.4 Stabilizers of U1 snRNP Recognition of the 5′‐Splice Site -- 7.3.5.5 Introduction to Spinal Muscular Atrophy (SMA) -- 7.3.5.6 Risdiplam (Evrysdi®) -- 7.4 Future Outlook -- References -- Chapter 8 Prospects for Riboswitches in Drug Development -- 8.1 Introduction -- 8.1.1 The Known Landscape of Riboswitches -- 8.1.2 Riboswitches in Drug Development. ; 8.1.3 The Need for Novel Antibiotics -- 8.2 Riboswitches as Drug Targets -- 8.2.1 Why Target Riboswitches? -- 8.2.2 Features of a Druggable Riboswitch -- 8.2.3 Riboswitch‐Targeted Drugs -- 8.2.3.1 Small Molecules Targeting FMN Riboswitches -- 8.2.3.2 Other Riboswitches Targeted in Proof‐of‐Principle Demonstrations -- 8.2.4 Barriers and Future Developments -- 8.3 Riboswitches as Tools for Antibiotic Drug Development -- 8.3.1 Riboswitches as Biosensors -- 8.3.2 A Riboswitch‐Based Fluoride Sensor Illuminates Agonists of Fluoride Toxicity -- 8.3.3 A Riboswitch‐Based ZTP Sensor Identifies Inhibitors of Folate Biosynthesis -- 8.3.4 A Riboswitch‐Based SAH Sensor Reveals an Inhibitor of SAH Nucleosidase -- 8.3.5 Barriers and Future Developments -- 8.4 Application of Riboswitches in Gene Therapy -- 8.4.1 Considerations for Designer Riboswitches -- 8.4.2 Eukaryotic Expression Platforms -- 8.4.3 Barriers and Future Developments -- 8.5 Concluding Remarks -- Acknowledgment -- References -- Chapter 9 Small Molecules That Degrade RNA -- 9.1 Antisense Oligonucleotide Degraders -- 9.2 Small‐Molecule Direct Degraders -- 9.2.1 N‐Hydroxypyridine‐2(1H)‐thione (N‐HPT) Conjugates -- 9.2.2 Bleomycin -- 9.2.3 Bleomycin Conjugates -- 9.2.3.1 Bleomycin Degraders Targeting the r(CUG) Repeat Expansion That Causes DM1 -- 9.2.3.2 Bleomycin Degraders Targeting r(CCUG) Repeat Expansion that Causes DM2 -- 9.2.3.3 Bleomycin Degraders Targeting Oncogenic Precursor microRNAs -- 9.2.3.4 Conclusions and Outlook for Bleomycin‐Based Direct Degraders -- 9.3 Ribonuclease Targeting Chimeras (RiboTACs) -- 9.3.1 RNase L is an Endogenous Endoribonuclease That Functions as Part of the Innate Immune Response -- 9.3.2 First‐Generation RiboTACs Targeting Oncogenic miRNAs -- 9.3.3 Small‐Molecule‐Based RiboTACs -- 9.3.4 Comparison of Bleomycin‐Based Direct Degraders and RiboTACs. ; 9.3.5 Discovery of Additional Small‐Molecule RNase L Activators -- 9.3.6 Conclusions and Outlook for RiboTACs -- 9.4 Summary and Outlook for Small‐Molecule RNA Degraders -- References -- Chapter 10 Approaches to the Identification of Molecules Altering Programmed Ribosomal Frameshifting in Viruses -- 10.1 Introduction -- 10.2 Mechanisms of Frameshifting -- 10.3 Targeting Frameshifting in HIV -- 10.4 Targeting Frameshifting in SARS‐CoV‐1 and SARS‐CoV‐2 -- 10.5 Conclusions -- References -- Chapter 11 RNA-Protein Interactions: A New Approach for Drugging RNA Biology -- 11.1 Molecular Basis of RNA-Protein Interactions -- 11.1.1 RNA Recognition Motifs (RRMs) -- 11.1.2 Double‐Stranded RNA‐Binding Domains (dsRBD) -- 11.1.3 Zinc Finger (ZnF) Domains -- 11.1.4 K Homology (KH) Domains -- 11.1.5 Other RBDs -- 11.2 Regulation and Dysregulation of RNA-Protein Interactions -- 11.2.1 Poor Quality Control Leads to Over‐ and Underproduction of RBPs -- 11.2.2 RBPs Become Out of Control, mRNA Processing Gets a Makeover (and Hates It) -- 11.2.3 RBP Shuttling of mRNA Becomes Askew -- 11.2.4 The RBP is Lost and Wreaks Havoc on the Cell -- 11.2.5 RBPs Dictate Which mRNAs are Translated, Favoring their Toxic Friends -- 11.2.6 RBPs and RNA Become Very Clique‐y, Form Their Own Complex and Cause Stress to the Rest of the Cell -- 11.3 Experimental Methods to Detect and Screen for Small Molecules that Modulate RNA-Protein Interactions -- 11.3.1 In vitro Fluorescence‐Based Assays -- 11.3.2 In vitro Chemiluminescence‐Based Assays -- 11.3.2.1 Cell‐Based RPI Detection Assays -- 11.3.3 Cell‐Based RNA-Protein Interaction Screening -- 11.4 Closing Remarks -- References -- Chapter 12 Drugging the Epitranscriptome -- 12.1 Introduction -- 12.2 Modifications on mRNA: N6‐Methyladenosine, Pseudouridine, and Inosine -- 12.2.1 N6‐Methyladenosine (m6A) -- 12.2.2 Pseudouridine (Ψ). ; 12.2.3 Inosine (I).
• Titolo autorizzato: RNA As a Drug Target
• ISBN: 9783527840434; 9783527351008
• Formato: Materiale a stampa
• Livello bibliografico: Monografia
• Lingua di pubblicazione: Inglese
• Record Nr.: 9910877076603321
• Lo trovi qui: Univ. Federico II
• Serie: Methods and Principles in Medicinal Chemistry Series