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.
• Sommario/riassunto: Hard-to-find insights from industry professionals on success strategies for developing the next generation of antiviral blockbuster drugs Presented by industry professionals with a track record of discovering new drugs and treatments, Trends in Antiviral Drug Development describes successful development efforts for antiviral compounds and therapies that have entered the market or are currently in clinical trials. Viruses are ordered by their target tissue, in line with contemporary drug development that focuses on tissue-targeted therapeutics. Other key trends in antiviral therapy, such as the effort to develop long-acting drugs, are described for each virus type, enabling readers to follow the current and future state in this core area of contemporary drug development. Trends in Antiviral Drug Development includes discussion on: Novel drugs against herpes viruses as well as the breakthrough drugs that cured HCV siRNA therapeutics, a new antiviral modality, and the drug candidates that are progressing toward achieving an HBV cure Drugs targeting viral entry, such as in HIV entry through attachment, co-receptor binding, and fusion Novel therapeutics against tropical diseases such as dengue fever and monkey pox Trends in Antiviral Drug Development is an essential read for medicinal chemists, pharmaceutical chemists, virologists, and all professionals seeking to understand new ideas and approaches to combat the ever-expanding universe of viral infections.
• 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