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.

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 ).

List of Contributors.

Preface.

A Personal Foreword.

1 Outlook of the Antiviral Drug Era, Now More Than 50 Years After Description of the First Antiviral Drug (Erik De Clercq).

1.1 Introduction: The Prehistory.

1.2 Key Events in Antiviral Drug Development.

1.3 Antiviral Drugs: Current State of the Art.

1.4 Antiviral Drugs Active against Herpesviruses (i.e., HSV, VZV, and so on).

1.5 Antiviral Drugs Active against Retroviruses (HIV).

1.6 Antiviral Drugs Active against Hepatitis B Virus .

1.7 Antiviral Drugs Active against DNA Viruses at Large.

1.8 Antiviral Drugs for Influenza A Virus Infections.

1.9 Antiviral Drugs for Hepatitis C Virus.

1.10 Antiviral Drugs for Poxviruses (i.e., Variola, Vaccinia, and so on).

1.11 Further Options to Treat Virus Infections.

1.12 Conclusions.

2 Inhibition of HIV Entry (José A. Esté).

2.1 Introduction.

2.2 The HIV Glycoproteins.

2.3 Mechanism of HIV Entry.

2.4 Inhibition of HIV Entry.

2.5 Concluding Remarks.

3 Targeting Integration Beyond Strand Transfer: Development of Second-Generation HIV Integrase Inhibitors (Arnout R.D. Voet, Marc De Maeyer, Frauke Christ, and Zeger Debyser).

3.1 HIV: The Causative Agent of AIDS.

3.2 The Integration Step: A Complex Mechanism with Different Possibilities for Inhibition.

3.3 DNA Binding Inhibitors.

3.4 Multimerization Inhibitors.

3.5 Targeting Integrase Cofactor Interactions.

3.6 Conclusion.

4 From Saquinavir to Darunavir: The Impact of 10 Years of Medicinal Chemistry on a Lethal Disease (Marie-Pierre de Béthune, Anik Peeters, and Piet Wigerinck).

4.1 Introduction.

4.2 The HIV Protease as a Target for AIDS.

4.3 The Early Protease Inhibitors.

4.4 The Medical Need for a "Next"-Generation PI.

4.5 How Can We Explain the Superior Antiviral Activity of Darunavir?

4.6 Clinical Development of Darunavir.

4.7 Conclusions and Future Developments.

5 Acyclic and Cyclic Nucleoside Phosphonates (Richard L. Mackman and Tomas Cihlar).

5.1 Introduction.

5.2 Nucleoside Phosphonate Strategy for Antivirals.

5.3 Acyclic Nucleoside Phosphonates.

5.4 Cyclic Nucleoside Phosphonates.

5.5 Prodrugs of Nucleoside Phosphonates.

5.6 Clinical Applications of Antiviral Nucleoside Phosphonates.

5.7 Conclusions.

6 Helicase–Primase Inhibitors: A New Approach to Combat Herpes Simplex Virus and Varicella Zoster Virus (Subhajit Biswas and Hugh J. Field).

6.1 Introduction.

6.2 The Role of Helicase Primase in the Replication of HSV.

6.3 Selective Inhibitors of Helicase Primase as Antiherpesvirus Antivirals.

6.4 HPIs are Effective in Cell Culture and In Vivo.

6.5 Effects of HPIs on the Establishment and Reactivation from Latency.

6.6 HPIs: The Biochemical Basis for the Proposed Mechanism of Action.

6.7 HSV Acquired Resistance to HPIs.

6.8 Patterns of Cross-Resistance.

6.9 Further Insight into Mode of HPI Interaction with the HSV HP Complex from the Study of Resistance Mutations.

6.10 The Frequency and Origin of HPI-Resistance Mutations.

6.11 UL5 Lys356Asn: a Mutation Conferring High Resistance to HPI.

6.12 The Origin of Resistance Mutations at High Frequency.

6.13 Conclusions.

7 Cyclophilin Inhibitors (Grégoire Vuagniaux, Arnaud Hamel, Rafael Crabbé, Hervé C. Porchet, and Jean-Maurice Dumont).

7.1 Introduction.

7.2 Cyclophilin Overview.

7.3 Cyclophilin Inhibitors Currently in Clinical Development.

7.4 Cyclophilin and HIV.

7.5 Cyclophilin and Hepatitis C.

7.6 Clinical Results in HCV.

7.7 Activity against Other Viruses.

7.8 New Noncyclosporine Cyclophilin Inhibitors.

7.9 Conclusion.

8 Alkoxyalkyl Ester Prodrugs of Antiviral Nucleoside Phosphates and Phosphonates (James R. Beadle and Karl Y. Hostetler).

8.1 Introduction.

8.2 Enhancing the Oral Activity of Antiviral Compounds: Overview of the Development of Alkoxyalkyl Esterification Approach.

8.3 Alkylglycerol and Alkoxyalkyl Prodrugs of Phosphonoformate: Enhanced Antiviral Activity and Synergism with AZT.

8.4 Alkoxyalkyl Esters of Nucleoside 50-Monophosphates.

8.5 Oral Prodrugs of Acyclic Nucleoside Phosphonates.

8.6 Intraocular Delivery of Antiviral Prodrugs for Treatment or Prevention of Cytomegalovirus Retinitis.

8.7 Conclusion.

9 Maribavir: A Novel Benzimidazole Ribonucleoside for the Prevention and Treatment of Cytomegalovirus Diseases (Karen K. Biron).

9.1 Cytomegalovirus Diseases: Unmet Challenges.

9.2 Maribavir: Antiviral Activity.

9.3 Maribavir: Mechanisms of Action and Resistance.

9.4 Preclinical Studies.

9.5 Clinical Development of Maribavir: Early Phase I.

9.6 Clinical Development in a Transplant Population.

9.7 Summary and Conclusions.

10 Anti-HCMV Compounds (Graciela Andrei and Robert Snoeck).

10.1 Introduction.

10.2 Anti-HCMV Drugs in Clinical Use.

10.3 Need for New Anti-HCMV Drugs.

10.4 Novel Viral Targets.

10.5 Cellular Targets.

10.6 Conclusions.

11 Lethal Mutagenesis as an Unconventional Approach to Combat HIV (Pinar Iyidogan and Karen S. Anderson).

11.1 Introduction.

11.2 Viral Fitness and Intrinsic Mutagenesis in RNA Viruses and Retroviruses.

11.3 Fundamentals of Lethal Mutagenesis.

11.4 Mutagenic Pharmaceuticals as Antiviral Agents.

11.5 KP-1212: From Bench to Clinic.

11.6 Challenges and Advantages of Lethal Mutagenesis Compared to Conventional Strategies.

11.7 Concluding Remarks and Future Perspectives.

12 Recent Progress in the Development of HCV Protease Inhibitors (Nagraj Mani, Bhisetti G. Rao, Tara L. Kieffer, and Ann D. Kwong).

12.1 Introduction.

12.2 HCV Therapy.

12.3 Mechanism of Resistance and Cross-Resistance to NS3 Protease Inhibitors.

12.4 Antiviral Potency and Clinical Efficacy of HCV Protease Inhibitors.

12.5 Future Directions.

13 Antiviral RNAi: How to Silence Viruses (Karin J. von Eije and Ben Berkhout).

13.1 The Discovery of RNA Interference.

13.2 Therapeutic Application of the RNAi Mechanism.

13.3 Mammalian Viruses and the RNAi Mechanism.

13.4 Basic Design of an RNAi Therapy against Viruses.

13.5 Selecting Optimal Targets.

13.6 Prevention of Viral Escape.

13.7 Multiplexing siRNAs.

13.8 Delivery Issues.

13.9 Potential Risks of an RNAi Therapy.

13.10 Example of an Acute Infection: RSV.

13.11 Example of a Chronic Infection: HIV-1.

13.12 Future Perspective.

14 Neuraminidase Inhibitors as Anti-Influenza Agents (Willard Lew, Michael Z. Wang, Xiaowu Chen, James F. Rooney, and Choung Kim).

14.1 Introduction.

14.2 Influenza Neuraminidase as a Drug Target.

14.3 Neuraminidase Active Site and Inhibitor Binding.

14.4 Small-Molecule Inhibitors of Influenza Neuraminidase.

14.5 Mechanism of Resistance.

14.6 Influenza Neuraminidase Inhibitors Based on Other Scaffolds.

14.7 Clinical Use of Neuraminidase Inhibitors.

14.8 Concluding Remarks.

15 From TIBO to Rilpivirine: The Chronicle of the Discovery of the Ideal Nonnucleoside Reverse Transcriptase Inhibitor (Erik De Clercq).

15.1 Introduction.

15.2 The TIBO Derivatives.

15.3 From Loviride to Rilpivirine.

15.4 Rilpivirine: How Does It Act?

15.5 Clinical Proof of Concept.

15.6 Pharmacokinetics and Drug–Drug Interactions.

15.7 Potency and Resilience to NNRTI Resistance.

15.8 Conclusion.

References.

Index.