Antiviral Drug Strategies

By focusing on general molecular mechanisms of antiviral drugs rather than therapies for individual viruses, this ready reference provides the critical knowledge needed to develop entirely novel therapeutics and to target new viruses.It begins with a general discussion of antiviral strategies, followed by a broad survey of known viral targets, such as reverse transcriptases, proteases, neuraminidases, RNA polymerases, helicases and primases, as well as their known inhibitors. The final section contains several cases studies of recent successful antiviral drug development.Edited by Erik de Clercq, the world authority on small molecule antiviral drugs, who has developed more new antivirals than anyone else.

List of contents

PrefaceOUTLOOK OF THE ANTIVIRAL DRUG ERA, NOW MORE THAN 50 YEARS AFTER DESCRIPTION OF THE FIRST ANTIVIRAL DRUGIntroduction: The PrehistoryKey Events in Antiviral Drug DevelopmentAntiviral Drugs: Current State of the ArtAntiviral Drugs Active against Herpesviruses (i.e., HSV, VZV, and so on)Antiviral Drugs Active against Retroviruses (HIV)Antiviral Drugs Active against Hepatitis B VirusAntiviral Drugs Active against DNA Viruses at LargeAntiviral Drugs for Influenza A Virus InfectionsAntiviral Drugs for Hepatitis C VirusAntiviral Drugs for Poxviruses (i.e., Variola, Vaccinia, and so on)Further Options to Treat Virus InfectionsConclusionsINHIBITION OF HIV ENTRYIntroductionThe HIV GlycoproteinsMechanism of HIV EntryInhibition of HIV EntryConcluding RemarksTARGETING INTEGRATION BEYOND ATRAND TRANSFER: DEVELOPMENT OF SECOND-GENERATION HIV INTEGRASE INHIBITORSHIV: The Causative Agent of AIDSThe Integration Step: A Complex Mechanism with Different Possibilities for InhibitionDNA Binding InhibitorsMultimerization InhibitorsTargeting Integrase Cofactor InteractionsConclusionFROM SAQUINAVIR TO DARUNAVIR: THE IMPACT OF 10 YEARS OF MEDICINAL CHEMISTRY ON A LETHAL DISEASEIntroductionThe HIV Protease as a Target for AIDSThe Early Protease InhibitorsThe Medical Need for a "Next"-Generation PIHow Can We Explain the Superior Antiviral Activity of Darunavir?Clinical Development of DarunavirConclusions and Future DevelopmentsACYCLIC AND CYCLIC NUCLEOSIDE PHOSPHONATESIntroductionNucleoside Phosphonate Strategy for AntiviralsAcyclic Nucleoside PhosphonatesCyclic Nucleoside PhosphonatesProdrugs of Nucleoside PhosphonatesClinical Applications of Antiviral Nucleoside PhosphonatesConclusionsHELICASE-PRIMASE INHIBITORS: A NEW APPROACH TO COMBAT HERPES SIMPLEX VIRUS AND VARICELLA ZOSTER VIRUSIntroductionThe Role of Helicase Primase in the Replication of HSVSelective Inhibitors of Helicase Primase as Antiherpesvirus AntiviralsHPIs are Effective in Cell Culture in In VivoEffects of HPIs on the Establishment and Reactivation from LatencyHPIs: The Biochemical Basis for the Proposed Mechanism of ActionHSV Acquired Resistance to HPIsPatterns of Cross-ResistanceFurther Insight into Mode of HPI Interaction with the HSV HP Complex from the Study of Resistance MutationsThe Frequency and Origin of HPI-Resistance MutationsUL5 Lys356Asn: A Mutation Conferring High Resistance to HPIThe Origin of Resistance Mutations at High FrequencyConclusionsCYCLOPHILIN INHIBITORSIntroductionCyclophilin OverviewCyclophilin Inhibitors Currently in Clinical DevelopmentCyclophilin and HIVCyclophilin and Hepatitis CClinical Results in HCVActivity against Other VirusesNew Noncyclosporine Cyclophilin InhibitorsConclusionALKOXYALKYL ESTER PRODRUGS OF ANTIVIRAL NUCLEOSIDE PHOSPHATES AND PHOSPHONATESIntroductionEnhancing the Oral Activity of Antiviral Compounds: Overview of the Development of Alkoxyalkyl Esterification ApproachAlkylglycerol and Alkoxyalkyl Prodrugs of Phosphonoformate: Enhanced Antiviral Activity and Synergism with AZTAlkoxyalkyl Esters of Nucleoside 5'-MonophosphatesOral Prodrugs of Acyclic NucleosideIntraocular Delivery of Antiviral Prodrugs for Treatment of Prevention of Cytomegalovirus RetinitisConclusionMARIBAVIR: A NOVEL BENZIMIDAZOLE RIBONUCLEOSIDE FOR THE PREVENTION AND TREATMENT OF CYTOMEGALOVIRUS DISEASESCytomegalovirus Diseases: Unmet ChallengesMaribavir: Antiviral ActivityMaribavir: Mechanisms of Action and ResistancePreclinical StudiesClinical Development of Maribavir: Early Phase IClinical Development in a Transplant PopulationSummary and ConclusionsANTI-HCMV COMPOUNDSIntroductionAnti-HCMV Drugs in Clinical UseNeed for New Anti-HCMV DrugsNovel Viral TargetsCellular TargetsConclusionsLETHAL MUTAGENESIS AS AN UNCONVENTIONAL APPROACH TO COMBAT HIVIntroductionViral Fitness and Intrinsic Mutagenesis in RNA Viruses and RetrovirusesFundamentals of Lethal MutagenesisMutagenic Pharmaceuticals as Antiviral AgentsKP-1212: From Bench to ClinicChallenges and Advantages of Lethal Mutagenesis Compared to Conventional StrategiesConcluding Remarks and Future PerspectivesRECENT PROGRESS IN THE DEVELOPMENT OF HCV PROTEASE INHIBITORSIntroductionHCV TherapyMechanism of Resistance and Cross-Resistance to NS3 Protease InhibitorsAntiviral Potency and Clinical Efficacy of HCV Protease InhibitorsFuture DirectionsANTIVIRAL RNAi: HOW TO SILENCE VIRUSESThe Discovery of RNA InterferenceTherapeutic Application of the RNAi MechanismMammalian Viruses and the RNAi MechanismBasic Design of an RNAi Therapy against VirusesSelecting Optimal TargetsPrevention of Viral EscapeMultiplexing siRNAsDelivery IssuesPotential Risks of an RNAi TherapyExample of an Acute Infection: RSVExample of a Chronic Infection: HIV-1Future PerspectiveNEURAMINIDASE INHIBITORS AS ANTI-INFLUENZA AGENTSIntroductionInfluenza Neuraminidase as a Drug TargetNeuraminidase Active Site and Inhibitor BindingSmall-Molecule Inhibitors of Influenza NeuraminidaseMechanism of ResistanceInfluenza Neuraminidase Inhibitors Based on Other ScaffoldsClinical Use of Neuraminidase InhibitorsConcluding RemarksFROM TIBO TO RILPIVIRINE: THE CHRONICLE OF THE DISCOVERY OF THE IDEAL NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORSIntroductionThe TIBO DerivativesFrom Loviride to RilpivirineRilpivirine: How Does It Act?Clinical Proof of ConceptPharmacokinetics and Drug-Drug InteractionsPotency and Resilience to NNRTI ResistanceConclusion

About the author

Erik De Clercq, M.D., PhD is currently President of the Rega Foundation, a member of the Belgian (Flemish) Royal Academy of Medicine and of the Academia Europaea, and a Fellow of the American Association for the Advancement of Science. He is an active Emeritus Professor of the Katholieke Universiteit Leuven (K.U.Leuven), Belgium. He is honorary doctor of the Universities of Ghent, Belgium, Athens, Greece, Ferrara, Italy, Jinan (Shandong), China, Charles (Prague), Czech Republic, and Jihoceska (Bude?jovice), Czech Republic.§For his pioneering efforts in antiviral research, Professor De Clercq received in 1996 the Aventis award from the American Society for Microbiology, and in 2000 the Maisin Prize for Biomedical Sciences from the Belgian National Science Foundation. In 2008 he was elected Inventor of the Year by the European Union. Together with Dr. Anthony Fauci, Prof. De Clercq received the Dr. Paul Janssen Award for Biomedical Research in 2010.§He is the (co)inventor of a number of antiviral drugs, used for the treatment of HSV (valaciclovir, Valtrex , Zelitrex ), VZV (brivudin, Zostex , Brivirac , Zerpex ), CMV (cidofovir, Vistide ), HBV (adefovir dipivoxil, Hepsera ), and HIV infections (AIDS) (tenofovir disoproxil fumarate, Viread ).

Hugo Kubinyi gehört seit 1985 der BASF AG an, wo Kombinatorische Chemie, Molecular Modelling und Wirkstoffdesign zu seinen Tätigkeitsfeldern zählten. Sein Spezialgebiet sind Struktur-Wirkungs-Beziehungen und QSAR-Methoden.

Gerd Folkers is professor of pharmaceutical chemistry at the ETH Zürich since 1991. He studied pharmacy at the University of Bonn and earned his Ph.D. on structure-activity relationships of desapurines. He then moved to the University of Tübingen, where he completed his habilitation in pharmaceutical chemistry. During a stay with H.-D. Hoeltje in Bern, he studied new research methods in computer-aided molecular design and expanded this knowledge during other stays with T. Blundell at the Birkbeck College and E. Meyer at Texas A&M University.The focus of his research is the molecular interaction between drugs and their binding sites. Besides his work on the molecular mechanism of "conventional" nucleoside therapeutics against virus infections and cancer, his special interest has shifted to immuno-therapeutics.

Summary

By focusing on general molecular mechanisms of antiviral drugs rather than therapies for individual viruses, this ready reference provides the critical knowledge needed to develop entirely novel therapeutics and to target new viruses.
It begins with a general discussion of antiviral strategies, followed by a broad survey of known viral targets, such as reverse transcriptases, proteases, neuraminidases, RNA polymerases, helicases and primases, as well as their known inhibitors. The final section contains several cases studies of recent successful antiviral drug development.
Edited by Erik de Clercq, the world authority on small molecule antiviral drugs, who has developed more new antivirals than anyone else.

Report

"Overall, the book is a clear success and represents an excellent and valuable treatise on current antiviral drug strategies. It is a must for all medicinal chemists interested in the field of antiviral chemotherapy, and it would be a good acquisition for both institutional and personal libraries, alike." (ChemMedChem, 2012)

Product details

• Authors: Erik De Clercq, Gerd Folkers, Hugo Kubinyi, Raimund Mannhold
• Assisted by: Erik De Clercq (Editor), Gerd Folkers (Editor), Hugo Kubinyi (Editor), Hugo Kubinyi et al (Editor), Raimun Mannhold (Editor), Raimund Mannhold (Editor), Gerd Folkers (Editor of the series), Hugo Kubinyi (Editor of the series), Raimund Mannhold (Editor of the series)
• Publisher: Wiley-VCH
• Languages: English
• Product format: Hardback
• Released: 31.03.2015
• EAN: 9783527326969
• ISBN: 978-3-527-32696-9
• No. of pages: 406
• Dimensions: 177 mm x 243 mm x 24 mm
• Weight: 938 g
• Illustrations: 68 SW-Abb., 39 Farbabb., 28 Tabellen
• Series: Methods and Principles in Medicinal Chemistry; Methods and Principles in Medicinal Chemistry
• Subjects: Natural sciences, medicine, IT, technology > Chemistry; Chemie, Virologie, Life Sciences, Wirkstoffforschung, Biowissenschaften, chemistry, Virology, Wirkstoffforschung u. -entwicklung, Drug Discovery & Development