Chemotherapy of Viral Infections by M.J. BartkowskiChemotherapy of Viral Infections by M.J. Bartkowski

Chemotherapy of Viral Infections

byM.J. Bartkowski, S. Bridges, P.E. Came

Paperback | December 7, 2011

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" . . . the motto for the therapeutics of the future will have to be de sedibus et causis pharmacorum. " P. EHRLICH, 1909 Exciting events in the basic disciplines of virology, immunology, and pharmacology continue to advance the understanding of the pathogenesis and control of virus diseases. At the same time, the rational development of antiviral agents is attracting, to an increasing extent, the interest of workers in other disciplines. Improvements in technology facilitate the definition of potential target sites for antiviral intervention and unmask new viral and host genes. The outcome is a further steady development of new antiviral agents which approach the "magic bullets" first proposed by PAUL EHRLICH. Remarkable advances in protein synthetic methods that yield polypeptides which inhibit active sites of viral proteins have aided substantially in the basic and clinical study of these antiviral agents. In addition, the extremely rapid progression in recombinant DNA techniques, leading to the synthesis of large quantities of gene products, is also increasing our opportunities at a dashing pace. New information and developing technology facilitate research on the mechanism of action, toxicity, pharmacokinetics, and pharmacodynamics of new agents. The list of clinically effective antiviral agents is expanding and the number of potentially useful compounds is growing rapidly. This book is a combined theoretical text and practical manual which, it is hoped, will be of use to all who have an interest in virus diseases, particularly scientists, physicians and graduate students.
Title:Chemotherapy of Viral InfectionsFormat:PaperbackDimensions:563 pages, 24.4 × 17 × 1.73 inPublished:December 7, 2011Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:3642684890

ISBN - 13:9783642684890

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Table of Contents

1 Pathogenesis of Viral Infections.- A. Introduction.- I. Defective Interfering Particles.- II. Integration of Viral Genomes.- B. Adenoviruses.- I. Structure and Replication.- II. Adenovirus Infections.- C. Arenaviruses.- D. Coronaviruses.- E. Viral Hepatitis.- I. Hepatitis A.- II. Hepatitis B.- F. Herpesviruses.- I. Herpes Simplex Viruses 1 and 2.- II. Herpes Simplex Virus Infections.- III. Cytomegalovirus.- IV. Varicella Zoster Virus.- V. Epstein-Barr Virus.- G. Orthomyxoviruses.- I. Influenza A and B Viruses.- II. Influenza C Virus.- III. Influenza Infections.- H. Human Papillomavirus.- J. Paramyxoviruses.- I. Measles Infection.- II. Persistent Measles Infection.- III. Mumps Infection.- IV. Parainfluenza Infection.- K. Picornaviruses.- I. Structure and Replication.- II. Picornavirus Infections.- L. Reoviruses.- M. RNA Tumor Viruses.- N. Rhabdoviruses.- I. Structure and Replication.- II. Rabies Virus Infection.- O. Rotaviruses.- I. Structure and Replication.- II. Rotavirus Infections.- P. Poxviruses.- I. Structure and Replication.- II. Poxvirus Infections.- Q. Togaviruses and Bunyaviruses.- I. Togaviruses.- II. Bunyaviruses.- R. Slow Viruses.- I. Unconventional Agents.- II. Conventional Agents.- References.- A.- 2 Pyrimidine Nucleosides with Selective Antiviral Activity.- A. Introduction.- B. 5-Halogenated Pyrimidine 2?-Deoxyribonucleosides.- I. 5-Iodo-2?-Deoxyuridine.- 1. Synthesis.- 2. Antiviral Activity.- 3. Effects on Normal Cells.- 4. Mechanism of Action.- II. 5-Trifluoromethyl-2?-Deoxyuridine.- 1. Synthesis.- 2. Antiviral Activity.- 3. Effects on Normal Cells.- 4. Mechanism of Action.- III. 5-Iodo-2?-Deoxycytidine.- 1. Synthesis.- 2. Antiviral Activity.- 3. Effects on Normal Cells.- 4. Mechanism of Action.- C. Other 5-Substituted 2?-Deoxyuridine Derivatives.- I. 5-Ethyl-2?-Deoxyuridine.- 1. Antiviral Activity.- 2. Effects on Normal Cells.- 3. Mechanism of Action.- II. 5-Propyl-2?-Deoxyuridine.- 1. Antiviral Activity.- 2. Mechanism of Action.- III. E-5-(2-Bromovinyl)-2?-Deoxyuridine (BVdUrd).- IV. 5-Methoxymethyl-2?-Deoxyuridine.- V. Miscellaneous 5-Substituted 2?-Deoxyuridine Derivatives.- D. Pyrimidine Nucleosides with an Altered Ring Structure.- E. Pyrimidine Nucleosides with an Altered Carbohydrate Moiety.- I. Arabinofuranosyltyymine.- 1. Antiviral Activity.- 2. Effects on Normal Cells.- 3. Mechanism of Action.- II. Arabinofuranosylcytosine.- III. 5-Iodo-5?-Amino-2?,5?-Dideoxyuridine.- 1. Synthesis.- 2. Antiviral Activity.- 3. Mechanism of Action.- IV. 1-(2-Deoxy-2-Fluoro-?-D-Arabinofuranosyl)-5-Iodocytosine.- References.- 3 Purines.- A. Introduction.- B. 9-?-D-Arabinofuranosyladenine.- I. Introduction and History.- II. Chemistry.- III. Antiviral Spectrum.- IV. Mechanism of Action.- V. Metabolism, Distribution, and Excretion.- VI. Clinical and Experimental Therapeutic Aspects.- VII. Untoward Effects.- VIII. Analogs of Ara-A.- IX. Perspectives.- C. 9-(2-Hydroxyethoxymethyl)guanine.- I. Introduction and History.- II. Chemistry.- III. Antiviral Spectrum.- IV. Mechanism of Action.- V. Metabolism, Distribution, and Excretion.- VI. Clinical and Experimental Therapeutic Aspects.- VII. Untoward Effects.- VIII. Perspectives.- References.- 4 Amantadine and Its Derivatives.- A. Introduction and History.- B. Chemical Structure.- C. Spectrum of Antiviral Activity.- D. Mechanism of Action.- E. Pharmacology.- I. Absorption.- II. Metabolism.- III. Side Effects.- F Animal Studies.- I. Prophylaxis.- II. Treatment.- G. Clinical Trials.- I. Prophylaxis.- II. Treatment.- H. Resistant Variants.- J. Conclusions and Perspectives.- References.- 5 The Thiosemicarbazones.- A. Introduction.- B. History.- C. Chemistry.- I. Aryl Thiosemicarbazones.- II. Quinoline, Pyridine, and Thiophene Thiosemicarbazones.- III. Isatin-?-Thiosemicarbazones.- 1. Substitution in the Aromatic Ring.- 2. N-Substitution in the Pyrrolidine Ring.- 3. Modification of the Pyrrolidine Ring.- 4. Modification of the TSC Side Chain.- 5. Other Compounds.- IV. Isatin-?-4?,4?-Dialkylthiosemicarbazones.- V. Isatin-?-Isothiosemicarbazones.- VI. Thiazole Thiosemicarbazones.- VII. Pyrrolidine and Pyrazolone Thiosemicarbazones.- VIII. Noncyclic Thiosemicarbazones.- IX. Miscellaneous Thiosemicarbazones.- D. Virus-Inhibitory Spectrum.- I. Aryl Thiosemicarbazones.- II. Quinoline, Pyridine, and Thiophene Thiosemicarbazones.- III. Isatin-?-Thiosemicarbazones.- IV. Isatin-?-4?,4?-Dialkylthiosemicarbazones.- V. Isatin-?-Isothiosemicarbazones.- VI. Thiazole Thiosemicarbazones.- VII. Pyrrolidine and Pyrazolone Thiosemicarbazones.- VIII. Noncyclic Thiosemicarbazones.- IX. Miscellaneous Thiosemicarbazones.- E. Effects on Normal Cells.- I. Aryl Thiosemicarbazones.- II. Quinoline, Pyridine, and Thiopene Thiosemicarbazones.- III. Isatin-?-Thiosemicarbazones.- IV. Isatin-?-4?, 4?-Dialkylthiosemicarbazones.- V. Isatin-?-Isothiosemicarbazones.- VI. Thiazole Thiosemicarbazones.- VII. Pyrrolidine and Pyrazolone Thiosemicarbazones.- VIII. Noncyclic Thiosemicarbazones.- IX. Miscellaneous Thiosemicarbazones.- F. Mechanism of Action.- I. Aryl Thiosemicarbazones.- II. Quinoline, Pyridine, and Thiopene Thiosemicarbazones.- III. Isatin-?-Thiosemicarbazones.- 1. Adsorption, Penetration, and Uncoating.- 2. Transcription.- 3. Translation.- 4. Replication.- 5. Proteins and Viral Assembly.- IV. Isatin-?-4?,4?-Dialkylthiosemicarbazones.- V. Isatin-?-Isothiosemicarbazones.- VI. Thiazole Thiosemicarbazones.- VII. Pyrrolidine and Pyrazolone Thiosemicarbazones.- VII. Noncyclic Thiosemicarbazones.- IX. Miscellaneous Thiosemicarbazones.- G. Animal Studies.- I. Aryl Thiosemicarbazones.- II. Quinoline, Pyridine, and Thiophene Thiosemicarbazones.- III. Isatin-?-Thiosemicarbazones.- IV. Isatin-?-4?,4?-Dialkylthiosemicarbazones.- V. Isatin-?-Isothiosemicarbazones.- VI. Thiazole Thiosemicarbazones.- H. Clinical Studies.- I. N1-Methylisatin-?-Thiosemicarbazone.- II. 3-Methyl-4-Bromo-5-Formylisothiazole Thiosemicarbazone.- J. Perspectives.- References.- 6 Interferon and Its Inducers.- A. Preface.- B. Introduction.- C. Production and Characterization of Human Interferons.- I. Classification.- II. Assay.- III. Production.- 1. Human Leukocyte Interferon.- 2. Human Fibroblast Interferon.- 3. Human Lymphoblastoid Interferon.- 4. Alternative Sources.- IV. Characterization.- 1. Protein Purification and Sequencing.- 2. Cloning of cDNA Corresponding to Interferon mRNA Species.- V. Mechanisms of Interferon Induction.- 1. General Comments.- 2. Interferon Induction by Viral Inducers.- 3. Interferon Induction by Synthetic Polynucleotides.- 4. Interferon Induction by Other Stimuli.- 5. Genetics of Interferon Induction.- 6. Characterization of Interferon mRNA Species and Their Transcription Units.- VI. The Regulation of Interferon Production.- 1. Priming.- 2. Superinduction.- D. Spectrum of Antiviral Activity.- E. Mechanisms of Antiviral Action of Interferon.- I. Interferon Binding.- II. Induction of the Antiviral State.- III. Effects on the Cell Surface.- IV. Effects on Translation-Inhibitory Enzymes.- 1. Oligo(A) Synthetase.- 2. dsRNA-Dependent Kinase.- 3. Cap Methylation of Viral mRNA.- 4. The tRNA Effect.- 5. Postscript: The Problem of Selectivity.- V. Effects of Interferon in Various Virus-Host Cell Systems.- 1. Viral Uncoating.- 2. Viral Transcription.- 3. Viral Protein Synthesis.- 4. Viral Assembly or Release.- F. Diversity of Interferon Action: Effects on Normal and Transformed Cells.- I. Cell Proliferation.- II. Cell Functions.- G. Pharmacokinetics of Interferons.- H. Efficacy of Interferons in Animal Models.- I. Antiviral Studies.- II. Antitumor Studies.- 1. Virus-Induced Tumors.- 2. Virus- and Radiation-Related "Spontaneous" Tumors.- 3. Transplantable Tumors.- II. Toxicity of Interferon in Animals.- J. Efficacy of Interferons in Humans.- I. Antiviral Studies.- II. Antitumor Studies.- III. Toxicity of Interferon in Humans.- K. Interferon Inducers.- I. High Molecular Weight Substances.- 1. Antiviral Effects.- 2. Antitumor Effects.- II. Low Molecular Weight Substances.- 1. Antiviral Effects.- 2. Antitumor Effects.- L. Perspectives.- References.- 7 Immunotherapy and Immunoregulation.- A. Introduction.- B. Immunity and Virus Infections.- C. Antiviral Agents.- I. Microbial Products.- 1. Protozoa.- 2. Gram-Negative Bacteria.- 3. Gram-Positive Bacteria.- 4. Mycobacteria.- II. Products of the Immune System.- 1 Immune Globulins.- 2. Thymic Hormones.- 3. Transfer Factor.- 4. Immune RNA.- 5. Interferon.- III. Synthesized Immunostimulants.- 1. Levamisole.- 2. Vitamins.- 3. Tilorone.- 4. Pyran.- 5. Inosiplex (Isoprinosine).- D. Potential of Immunostimulants as Antiviral Agents.- References.- B.- 8 Guanidine.- A. Introduction and History.- B. Synthesis and Properties of Picornavirus Proteins.- I. "Shutoff" of Host Cell Protein Synthesis.- II. Synthesis of Viral Proteins.- III. Mapping of the Viral Genome.- IV. Isolation of Viral Polypeptides.- C. Replication of Viral RNA.- I. Viral RNA Structure.- II. Viral Polymerase.- D. Chemistry of Guanidine.- E. Effects of Guanidine on Virus Replication.- I. Spectrum of Inhibited Viruses.- II. Effects on Cells.- III. Stage of Viral Growth Inhibited by Guanidine.- IV. Guanidine-Suppressive Compounds.- V. Site of Action of Guanidine.- VI. Mechanism of Action of Guanidine.- 1. Previous Studies.- 2. Effects on Poliovirus Polymerase in Vitro.- 3. Probable Mode of Action of Guanidine.- F. Guanidine as a Therapeutic Agent in Animals.- G. Clinical Nonvirologic Studies.- References.- 9 Benzimidazoles.- A. Introduction and Historical Remarks.- B. 2-(?-Hydroxybenzyl)-Benzimidazole.- I. Virus-Inhibitory Spectrum.- II. Effects of HBB on Uninfected Cells.- III. Kinetics of Antiviral Action, Effects on Viral Replication, and Mechanism of Action.- 1. Kinetic Aspects of Action.- 2. Effects on the Virus Replication Cycle.- 3. Mechanism of Action.- IV. HBB Resistance and Dependence: Genetics of the System.- V. Rescue.- VI. Superadditive Antiviral Effects of HBB and Guanidine.- VII. Effects of HBB on Enterovirus-Infected Cells.- C. HBB and Guanidine Chemotherapy in Animals.- I. Description of the Mouse System: Successful Treatment of Enterovirus-Infected Animals.- II. Failure of Drug-Resistant Mutants to Emerge in Animals.- III. The Importance of Drug Distribution, Metabolism, and Elimination on Therapeutic Efficacy.- 1. Introduction.- 2. Distribution and Excretion of HBB in the Mouse: Effects of Age.- 3. Metabolic Pathway of HBB in the Mouse and in Isolated Hepatocytes.- 4. Distribution and Excretion of Guanidine • HC1 in the Mouse.- 5. Experiments to Define Optimum Treatment.- 6. Treatment of Mice Infected with Coxsackievirus B4 and Polio-virus 2.- 7. Late Treatment When First Symptoms Have Appeared: Combined Effects of D-HBB, Guanidine, and Virus-Specific Antiserum.- D. Chemical Derivatives of HBB and Their Antiviral Activity in Cell Culture and in the Organism.- I. Structure-Activity Studies.- II. 1-Propyl-2-(?-Hydroxylbenzyl)-Benzimidazole (1-Propyl-HBB) and Its Hydrochloride Salt.- III. 2-(a-Methyl-?-Hydroxybenzyl)-Benzimidazole Hydrochloride (a-Methyl-HBB • HC1).- IV. 1,2-bis-(5-Methoxy-2-Benzimidazolyl)-1,2-Ethanediol (1,2-bisBenzimidazole).- V. 2-Amino-1-(Isopropylsulfonyl)-6-Benzimidazole Phenyl Ketone Oxime.- E. Conclusions.- References.- 10 Arildone: A ?-Diketone.- A. Introduction.- B. Chemical Structure and Synthesis.- C. Antiviral Effects.- I. In Vitro Studies.- 1. Inhibition of Cytopathic Effects in Cell Culture.- 2. Plaque Reduction Tests.- 3. Effect of Virus Yield.- II. In Vivo Studies Against Herpes.- 1. Arildone in DMSO.- 2. Arildone in Cream.- D. Mode of Action.- I. Herpes Simplex Virus.- II. Poliovirus.- E. Metabolism.- I. In Vitro Studies.- 1. Metabolism by CATR Cells.- II. In Vivo Studies.- 1. Disposition in Laboratory Animals.- 2. Metabolism in Laboratory Animals.- F. Toxicology.- I. In Vitro Studies.- 1. Mutagenic Evaluation of Arildone.- 2. Effect of Arildone on Cellular Macromolecular Synthesis.- 3. Effect of Arildone and Its Metabolites on Cell Growth.- II. In Vivo Studies.- G. Summary and Perspectives.- References.- 11 Phosphonoacetic Acid.- A. Introduction and History.- B. DNA Polymerases.- I. Cellular DNA Polymerases.- II. Herpesvirus DNA Polymerase.- C. Chemistry.- I. Structure.- II. Structure-Activity Relationships.- 1. Analogs.- 2. Phosphonoformic Acid.- D. Spectrum of Activity.- I. Virus Replication in Tissue Culture.- 1. Productive Infections.- 2. Transformed Cells.- II. Normal Cells.- III. Animal Models.- 1. Cutaneous Herpesvirus Infections.- 2. Ocular Herpesvirus Infections.- 3. Herpes Genitalis.- 4. Herpesvirus Infections of the Central Nervous System.- 5. Systemic Herpesvirus Infections.- 6. Latent Herpesvirus Infections.- 7. Varicella Infections.- 8. Lymphoproliferative Disease.- 9. Nonherpesvirus Infections.- 10. Summary.- E. Pharmacologic and Clinical Studies.- I. Metabolism.- II. Toxicology.- III. Clinical Pharmacology.- F. Mechanism of Action.- I. Inhibition of Herpesvirus-Induced DNA Polymerase.- II. Genetic Resistance.- G. Summary and Perspectives.- References.- 12 Natural Products.- A. Introduction.- B. Amino Acids.- I. Lysine.- II. Phenylalanine and Phenylalanine Analogs.- III. Methionine and Methionine Analogs.- IV. Miscellaneous Amino Acids and Analogs.- C. Vitamin C.- D. Flavonoids.- E. Polysaccharides.- I. Sulfated Polysaccharides.- II. Heparin.- III. Intestinal Mucopolysaccharides.- F. Substances from Microorganisms.- I. Fungal Products.- 1. Aphidicolin.- 2. Cordycepin.- 3. Cytochalasin B.- 4. Gliotoxin, Aranotin, Sporidesmin, and Chetomin.- 5. Mycophenolic Acid.- 6. Tenuazonic Acid.- II. Bacterial Products.- 1. Streptomyces.- 2. Other Bacteria.- G. Substances from Botanical Sources.- I. Alkaloids.- II. Tannins.- III. Lignosulfonates.- IV. Other Substances.- 1. ?-Aminitin.- 2. Calcium Elenolate.- 3. Glycyrrhizic Acid.- H. Substances from Marine Flora and Fauna.- I. Other Substances.- I. Vitamin A.- II. Milk.- III. Mosquito Tissues.- IV. Cobra Venom.- V. Neuraminidase Inhibitors.- References.- 13 Rifamycins.- A. Introduction.- B. Activity of Rifamycins on Bacteria.- I. Structural Requirements for Activity.- II. Mechanism of Inhibition of RNA Polymerase.- III. Effects on Psittacosis-Lymphogranuloma-Trachoma Agents.- C. Activity of Rifamycins on Bacterial Viruses.- I. Effect on DNA Bacteriophages.- II. Effect on RNA Bacteriophages.- D. Activity of Rifamycins on Mammalian Viruses.- I. Growth Inhibition of Mammalian Viruses by Rifampicin.- II. Mechanism of Vaccinia Virus Growth Inhibition by Rifampicin.- 1. Effect on DNA Synthesis of Vaccina-Infected Cells.- 2. Effect on mRNA Synthesis.- 3. Effect on Protein Synthesis.- 4. Effect on Virus Assembly.- 5. Inhibition of Precursor Polypeptide Cleavage.- 6. Antivaccinia Activity of Various Rifamycin Derivatives.- 7. Effect of Rifampicin on Experimental Vaccinia Infections.- III. Effect of Rifampicin on DNA Viruses Other Than Vaccinia.- 1. Herpesviruses.- 2. Adenoviruses.- IV. Effect of Rifampicin on RNA Viruses Other Than Retroviruses.- 1. Picornaviruses.- 2. Vesicular Stomatitis Virus.- V. Inhibition of Retrovirus Functions by Rifamycins.- 1. Search for Selective Inhibitors of the Reverse Transcriptase.- 2. Correlation Between Lipophilicity and Antipolymerase Activity.- 3. Mechanism of Inhibition of the Reverse Transcriptase.- 4. Effects of Rifamycins on Virus Replication and Cell Transformation.- E. Pharmacology of Rifampicin.- F. Antiviral Activity of Other Ansamycins.- I. Streptovaricins.- 1. Effects on Vaccinia Virus.- 2. Effect on Retrovirus Functions.- II. Tolypomycins.- III. Geldanamycin and Related Compounds.- G. Concluding Remarks.- References.