Chemotherapy of Viral Infections

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.