Antiviral Drug Strategies

InhaltsangabePreface OUTLOOK OF THE ANTIVIRAL DRUG ERA, NOW MORE THAN 50 YEARS AFTER DESCRIPTION OF THE FIRST ANTIVIRAL DRUG Introduction: The Prehistory Key Events in Antiviral Drug Development Antiviral Drugs: Current State of the Art Antiviral Drugs Active against Herpesviruses (i.e., HSV, VZV, and so on) Antiviral Drugs Active against Retroviruses (HIV) Antiviral Drugs Active against Hepatitis B Virus Antiviral Drugs Active against DNA Viruses at Large Antiviral Drugs for Influenza A Virus Infections Antiviral Drugs for Hepatitis C Virus Antiviral Drugs for Poxviruses (i.e., Variola, Vaccinia, and so on) Further Options to Treat Virus Infections Conclusions INHIBITION OF HIV ENTRY Introduction The HIV Glycoproteins Mechanism of HIV Entry Inhibition of HIV Entry Concluding Remarks TARGETING INTEGRATION BEYOND ATRAND TRANSFER: DEVELOPMENT OF SECOND-GENERATION HIV INTEGRASE INHIBITORS HIV: The Causative Agent of AIDS The Integration Step: A Complex Mechanism with Different Possibilities for Inhibition DNA Binding Inhibitors Multimerization Inhibitors Targeting Integrase Cofactor Interactions Conclusion FROM SAQUINAVIR TO DARUNAVIR: THE IMPACT OF 10 YEARS OF MEDICINAL CHEMISTRY ON A LETHAL DISEASE Introduction The HIV Protease as a Target for AIDS The Early Protease Inhibitors The Medical Need for a "Next"-Generation PI How Can We Explain the Superior Antiviral Activity of Darunavir? Clinical Development of Darunavir Conclusions and Future Developments ACYCLIC AND CYCLIC NUCLEOSIDE PHOSPHONATES Introduction Nucleoside Phosphonate Strategy for Antivirals Acyclic Nucleoside Phosphonates Cyclic Nucleoside Phosphonates Prodrugs of Nucleoside Phosphonates Clinical Applications of Antiviral Nucleoside Phosphonates Conclusions HELICASEPRIMASE INHIBITORS: A NEW APPROACH TO COMBAT HERPES SIMPLEX VIRUS AND VARICELLA ZOSTER VIRUS Introduction The Role of Helicase Primase in the Replication of HSV Selective Inhibitors of Helicase Primase as Antiherpesvirus Antivirals HPIs are Effective in Cell Culture in In Vivo Effects of HPIs on the Establishment and Reactivation from Latency HPIs: The Biochemical Basis for the Proposed Mechanism of Action HSV Acquired Resistance to HPIs Patterns of Cross-Resistance Further Insight into Mode of HPI Interaction with the HSV HP Complex from the Study of Resistance Mutations The Frequency and Origin of HPI-Resistance Mutations UL5 Lys356Asn: A Mutation Conferring High Resistance to HPI The Origin of Resistance Mutations at High Frequency Conclusions CYCLOPHILIN INHIBITORS Introduction Cyclophilin Overview Cyclophilin Inhibitors Currently in Clinical Development Cyclophilin and HIV Cyclophilin and Hepatitis C Clinical Results in HCV Activity against Other Viruses New Noncyclosporine Cyclophilin Inhibitors Conclusion ALKOXYALKYL ESTER PRODRUGS OF ANTIVIRAL NUCLEOSIDE PHOSPHATES AND PHOSPHONATES Introduction Enhancing the Oral Activity of Antiviral Compounds: Overview of the Development of Alkoxyalkyl Esterification Approach Alkylglycerol and Alkoxyalkyl Prodrugs of Phosphonoformate: Enhanced Antiviral Activity and Synergism with AZT Alkoxyalkyl Esters of Nucleoside 5'-Monophosphates Oral Prodrugs of Acyclic Nucleoside Intraocular Delivery of Antiviral Prodrugs for Treatment of Prevention of Cytomegalovirus Retinitis Conclusion MARIBAVIR: A NOVEL BENZIMIDAZOLE RIBONUCLEOSIDE FOR THE PREVENTION AND TREATMENT OF CYTOMEGALOVIRUS DISEASES Cytomegalovirus Diseases: Unmet Challenges Maribavir: Antiviral Activity Maribavir: Mechanisms of Action and Resistance Preclinical Studies Clinical Development of Maribavir: Early Phase I Clinical Development in a Transplant Population Summary and Conclusions ANTIHCMV COMPOUNDS Introduction AntiHCMV Drugs in Clinical Use Need for New Anti-HCMV Drugs Novel Viral Targets Cellular Targets Conclusions LETHAL MUTAGENESIS AS AN UNCONVENTIONAL APPROACH TO COMBAT HIV Introduction Viral Fitness and Intrins

New viruses can arise very quickly and, if unchecked, result in major pandemics. Obvious examples being the AIDS and SARS virus. In order to deal with such imminent threats, drug development times need to be cut short. This is only possible by relying on proven strategies and adapting them to the specific features of any new virus or virus variant. 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 is edited by Erik de Clercq, a world authority on antiviral drug discovery. The volume covers 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 book also contains several case studies of recent successful antiviral drug development. As a result, medicinal and pharmaceutical chemists, as well as virologists will be able to pinpoint strategies for combating future viral pandemics.

Outlook of the Antiviral Drug Era, now more than 50 Years after Description of the First Antiviral Drug Inhibition of HIV Entry Targeting Integration Beyond Strand Transfer. Development of Second Generation HIV Integrase Inhibitors From Saquinavir to Darunavir, the Impact of 10 Years of Medicinal Chemistry on a Lethal Disease Acyclic and Cyclic Nucleoside Phosphonates Helicase-Primase Inhibitors - A New Approach to Combat Herpes Simplex Virus and Varicella-Zoster Virus Cyclophilin Inhibitors Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates Maribavir: A Novel Benzimidazole Ribonucleoside for the Prevention and Treatment of Cytomegalovirus Diseases Anti-HCMV Compounds Lethal Mutagenesis as an Unconventional Approach to Combat HIV Recent Progess in the Development of HCV Protease Inhibitors Antiviral RNAi, How to Silence Viruses Neuraminidase Inhibitors as Anti-Influenza Agents From TIBO to Rilpivirine: The Chronicle of the Discovery of the Ideal Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI)