Trends in Antiviral Drug Development

• Autore: Sofia Michael J
• Pubblicazione: Newark : , : John Wiley & Sons, Incorporated, , 2025; ©2025
• Edizione: 1st ed.
• Descrizione fisica: 1 online resource (531 pages)
• Altri autori: WangZhengqiang FischerJános KleinChristian ChildersWayne E RotellaDavid P
• Nota di contenuto: Cover -- Half Title Page -- Title Page -- Copyright -- Contents -- Preface -- Introduction: Successes and Challenges in Antiviral Drug Development -- Introduction -- Antiviral Drugs Targeting Human Herpesviruses -- Antiviral Drugs Targeting Human Immunodeficiency Virus -- Drugs Targeting Reverse Transcriptase -- Drugs Targeting Protease -- Drugs Targeting Integrase Strand Transfer -- Drugs Targeting Viral Entry -- Drugs Targeting Viral Capsid -- Antiviral Drugs Targeting Hepatitis B Virus -- Antiviral Drugs Targeting Hepatitis Delta Virus -- Antiviral Drugs Targeting Hepatitis C Virus -- Antiviral Drugs Targeting Acute RNA Respiratory Viruses -- Drugs Targeting Human Influenza Viruses -- Drugs Targeting SARS-CoV-2 -- New Trends and Challenges in Antiviral Drug Development -- References -- Part I: Human Herpes Viruses -- Chapter 1: Letermovir for the Prevention of CMV Infection in Transplant Recipients -- 1.1 Background -- 1.1.1 Cytomegalovirus -- 1.1.2 Immunocompromised Patients -- 1.1.3 Patient Groups with a High Risk for CMV Complications -- 1.1.4 Available CMV Treatments Before Letermovir -- 1.1.4.1 Antiviral Drugs -- 1.1.4.2 Dominant Treatment Strategies -- 1.1.4.3 Unmet Medical Need -- 1.2 Discovery Phase -- 1.3 Preclinical Characterization -- 1.3.1 Antiviral Potency/Selectivity/Inhibitory Profile -- 1.3.1.1 In Vitro Potency Versus Laboratory CMV Strains -- 1.3.1.2 In Vitro Potency Versus Clinical CMV Isolates and Resistance-breaking Profile -- 1.3.1.3 In Vivo Efficacy (Xenotransplant Model) -- 1.3.1.4 In Vitro Antiviral Specificity -- 1.3.1.5 Other Characteristics of Letermovir's Inhibitory Profile -- 1.3.1.6 Summary -- 1.4 Mechanism of Action Studies -- 1.4.1 Target Identification -- 1.5 Terminase Inhibitors -- 1.5.1 Previous and Contemporary Drug Candidates Targeting the Terminase Complex. ; 1.5.2 Letermovir: Same Target, Different Interaction -- 1.5.3 Advantages of Terminase Inhibitors -- 1.6 Preclinical Safety Evaluation -- 1.7 Clinical Development and MAA/NDA Submission -- 1.7.1 Regulatory Support for Clinical Development -- 1.7.2 Phase 1 -- 1.7.2.1 Drug-Drug Interaction Studies -- 1.7.2.2 Special Populations -- 1.7.2.3 IV Formulation -- 1.7.3 Clinical Proof-of-concept -- 1.7.3.1 Phase 2a Clinical Trial (AIC001-2-001) -- 1.7.3.2 Emergency IND Treatment of a Lung Transplant Patient with Multiresistant CMV Disease -- 1.7.3.3 Credentials Established -- 1.7.4 Letermovir for CMV Prophylaxis in HSCT Patients -- 1.7.4.1 Phase 2b: First Prophylaxis Trial in HSCT Patients -- 1.7.4.2 Phase 3 CMV Prophylaxis Trial in HSCT Patients -- 1.7.4.3 Marketing Approval in HSCT Recipients -- 1.7.4.4 Further Clinical Development and Real-world Data -- 1.7.4.4.1 Phase 3 Trial for Extension of the Prophylaxis Period -- 1.7.4.4.2 Follow-up Trials in Specific Populations -- 1.7.5 Letermovir for CMV Prophylaxis in KT Patients -- 1.7.5.1 Phase 3 Noninferiority Trial in KT Recipients -- 1.7.5.2 Marketing Approval in KT Recipients -- 1.7.5.3 Further Clinical Development and Real-world Data -- 1.8 Drug Resistance -- 1.8.1 Genetic Characterization of Letermovir Resistance -- 1.9 Letermovir Resistance in Clinical Trials -- 1.10 Real-world Resistance -- 1.11 Outlook for Letermovir -- Acknowledgments -- References -- Chapter 2: Discovery and Development of the Helicase-Primase Inhibitor Pritelivir for the Treatment of Immunocompromised Patients with Resistant HSV Infection -- 2.1 HSV Virology and Disease -- 2.2 Treatment -- 2.3 Resistant Infections -- 2.4 Pritelivir Discovery and Target Identification -- 2.5 Nonclinical Data -- 2.5.1 In Vitro Studies -- 2.5.2 In Vivo Studies -- 2.5.2.1 Guinea Pig Model for Genital HSV-2 Infection -- 2.5.2.2 Mouse Model for HSE. ; 2.5.2.3 Pritelivir in Immunocompromised Mouse Model -- 2.6 Clinical Data -- 2.6.1 Phase 1 Program -- 2.6.2 Genital HSV -- 2.6.3 Resistant Infections -- 2.7 Pritelivir Resistance -- 2.8 Conclusion and Outlook -- References -- Part II: Immunodeficiency Virus -- Chapter 3: The Discovery and Early Development of the HIV-1 Integrase Strand Transfer Inhibitor Dolutegravir (S/GSK1349572) -- 3.1 Introduction -- 3.2 Medicinal Chemistry -- 3.2.1 Discovery of S/GSK1349572 (DTG) -- 3.2.1.1 Evolution of the Chemical Structure Leading to DTG -- 3.3 Virology -- 3.3.1 In Vitro Studies Indicated Robust Efficacy and High Barrier to Resistance of DTG -- 3.4 Clinical Development -- 3.4.1 PK Studies Supported Once-daily 50 mg Dosing of DTG -- 3.4.2 Clinical Studies in People Living with HIV-1 -- 3.4.3 Clinical Studies in Individuals with Prior Treatment Failure -- Acknowledgments -- References -- Chapter 4: The Discovery and Development of Islatravir (4'-Ethynyl-2-fluoro-2'-deoxyadenosine [EFdA], MK-8591) -- 4.1 Introduction -- 4.2 HIV Replication Cycle -- 4.3 Structure and Function of HIV RT -- 4.4 DNA Synthesis by RT -- 4.5 RT Inhibitor Classes -- 4.6 EFdA Development -- 4.6.1 4'-Ethynyl Ribose Modifications -- 4.6.2 2-Fluoro Adenosine Modifications -- 4.6.3 3'-Hydroxy Ribose Modification -- 4.7 EFdA: A Compound with 4'-Ethynyl, 2-Fluoro, and 3'-Hydroxy Modifications -- 4.7.1 Effects of the 4'-Ethynyl Modification on EFdA -- 4.7.2 Effects of the 2'-Fluoro Modification on EFdA -- 4.7.3 Effects of the 3'-Hydroxy Modification on EFdA -- 4.7.3.1 Mechanisms of Inhibition: EFdA -- 4.7.3.1.1 Biochemical Mechanisms of Inhibition -- 4.7.3.1.2 Structural Mechanisms of Inhibition -- 4.8 Mechanism of Resistance/Hypersusceptibility to EFdA -- 4.8.1 Mechanisms of Viral Resistance to EFdA -- 4.8.2 Mechanisms of Viral Hypersusceptibility to EFdA. ; 4.8.3 Combination Therapies with EFdA -- 4.8.4 Synthesis Advances -- 4.9 Animal Studies -- 4.9.1 EFdA Pharmacokinetic Studies in Rodents -- 4.9.2 EFdA Antiviral Activity in Humanized Mice -- 4.9.3 EFdA Antiviral Activity in Rhesus Macaques -- 4.9.4 EFdA Long-acting Activity in Various Animals -- 4.10 Clinical Trials -- 4.11 Long-acting Methods of Delivery for EFdA Treatment -- 4.12 NRTTIs as a Drug Class -- References -- Part III: Hepatitis Viruses -- Chapter 5: Discovery of the RNA Interference Therapeutic Imdusiran, a GalNAc-conjugated siRNA -- 5.1 Introduction -- 5.2 Comparison of Preclinical Anti-HBV Efficacy Between Lipid Nanoparticle-encapsulated and GalNAc-conjugated siRNA -- 5.3 Comparison of Tetravalent Versus Trivalent GalNAc Ligands -- 5.4 siRNA Selection: Comparison of siRNA Activity Against HBsAg and HBx Targets -- 5.5 Imdusiran Design and Preclinical Characterization -- 5.5.1 Abrogation of siRNA Immunostimulatory Potential -- 5.5.2 Imdusiran siRNA Target Site Sequence -- 5.6 Imdusiran Antiviral Activity -- 5.6.1 Imdusiran Antiviral Activity in Primary Mouse and Human Hepatocyte HBV Models -- 5.6.2 Imdusiran In Vivo Antiviral Activity -- 5.7 Imdusiran Combination Treatment -- 5.7.1 Imdusiran Combination with Standard of Care and Investigational Agents -- 5.8 Perspectives -- References -- Chapter 6: Discovery and Development of ARO-HBV/JNJ-3989 -- 6.1 Introduction -- 6.1.1 Chronic Hepatitis B Virus Infection -- 6.1.1.1 HBV Structure and Associated Molecular and Cellular Biology -- 6.1.1.1.1 Clinical Course of HBV Infection -- 6.2 Development of RNAi Therapeutic ARO-HBV/JNJ-73763989 (JNJ-3989) -- 6.2.1 RNAi as a Therapeutic Modality -- 6.2.2 Use of siRNA to Treat HBV Infection -- 6.2.2.1 JNJ-3989 siRNAs Have Broad Cross-reactivity to HBV Genotypes and HBV Transcripts. ; 6.2.2.1.1 Reduction of Serum HBsAg, HBeAg, and HBV DNA in Mouse Model of Chronic HBV Infection -- 6.3 Pharmacokinetics and Safety of JNJ-3989 in Humans -- 6.4 Clinical Studies in Chronically HBV-infected Patients -- 6.4.1 Direct Antiviral Treatment Approach with JNJ-3989-based Regimens -- 6.4.1.1 Pharmacological Response to JNJ-3989 with Short-term Treatment -- 6.4.1.2 REEF-1 Clinical Study -- 6.4.1.3 REEF-2 Clinical Study -- 6.4.2 Combination Approaches of JNJ-3989 with Immune Modulation -- 6.4.2.1 PENGUIN Clinical Study -- 6.4.2.2 REEF-IT Clinical Study -- 6.4.3 HBsAg Targeting siRNA JNJ-3989 in Chronic Hepatitis D -- 6.4.3.1 REEF-D Clinical Study -- 6.5 Discussion and Perspectives -- References -- Chapter 7: The Discovery and Development of Sofosbuvir as the Backbone of HCV Curative Therapies -- 7.1 Introduction -- 7.2 Identification of the 2'- -F, 2'-ß-C-Methyl Cytidine Nucleoside PSI-6130 -- 7.3 Identification of the 3',5'-Diisobutyrate Ester Prodrug RG7128 and Clinical Proof-of-concept -- 7.4 Development of the 5'-Phosphoramidate Uridine Nucleotide Prodrug for Liver Targeting and Clinical Proof-of-concept -- 7.5 Sofosbuvir: The Backbone of HCV Curative Therapies -- 7.6 Conclusion -- References -- Chapter 8: The Discovery and Development of Harvoni® and Epclusa®: Ending the Interferon Era -- Curing All Hepatitis C Genotypes -- 8.1 Cure -- 8.2 Introduction -- 8.3 The Discovery of Ledipasvir [13-15] -- 8.4 Early Development of Ledipasvir -- 8.5 Ledipasvir/Sofosbuvir STR Clinical Trial Results and Real-world Effectiveness -- 8.6 Initiation of a Pangenotypic NS5A Inhibitor Program -- 8.7 Discovery of the Pangenotypic NS5A Inhibitor Velpatasvir [40-42] -- 8.8 The Development of Velpatasvir -- 8.9 Clinical Trial Efficacy and Real-world Effectiveness with the Pangenotypic Sofosbuvir/Velpatasvir STR -- 8.10 Conclusion -- Acknowledgment. ; Compliance with Ethical Standards.
• Titolo autorizzato: Trends in Antiviral Drug Development
• ISBN: 3-527-84509-7; 3-527-84510-0; 3-527-84508-9
• Formato: Materiale a stampa
• Livello bibliografico: Monografia
• Lingua di pubblicazione: Inglese
• Record Nr.: 9911019658503321
• Lo trovi qui: Univ. Federico II
• Serie: Trends in Drug Discovery Series