Medical Pharmacology Chapter 36:  Antiviral Drugs

Antiviral Drugs Table of Contents

Viral Infections Influenza Viral Replication Steps Anti-herpes Drugs and related topics Acyclovir Mechanism of Action Selectivity Chemistry:  Acyclovir and Valacyclovir Formulations IV Acyclovir in Treating Mucocutaneous Herpes Simplex Virus (HSV) Infections in HIV patients Varicella-Zoster Virus (VZV) Treatment: Introduction Treatment of Genital Herpes Simplex Virus Infections Acyclovir-resistance in HIV:  Foscarnet Varicella-Zoster Virus  (VZV) Infection Acyclovir Summary:  Adverse Effects etc. Ganciclovir (Cytovene, Cymevine) Famciclovir (Famvir) Penciclovir (Denavir) Drug Resistance for Acyclovir and Acyclovir-Related Drugs Cidofovir (Vistide):  Principle of Action Cidofovir Pharmacology Clinical Case:  Intralesion  Cidofovir Treatment Fomivirsen Foscarnet (Foscavir) Kaposi's Sarcoma Trifluridine (Viroptic) Docosonal (Abreva) Idoxuridine (Dendra) Anti-Influenza Drugs and Related Topics Introduction Complications of Influenza Pneumonia Secondary Bacterial Pneumonia Orthomyxoviruses Influenza Viral Genome Segments Hemagglutinin and Viral Replication Nucleocapsid Release from the Virion Action of the Influenza Antiviral Drug Amantadine Viral RNA Replication Precursor Viral mRNA Capping Amantadine and Rimantadine Introduction Mechanism of Anti-Viral Action Drug Absorption and Elimination Adverse Effects Neuraminidase Inhibitors Short video on Influenza Virus Infection Introduction Oseltamivir and Zanamivir Corona Viral Biology and Possible Drug Treatment Anti-HIV Drugs Introduction:  Human Retroviruses HIV/AIDS in 2014: Progress and Priories: Video Presentation Pneumocystics jirovecii Pneumonia Kaposi's Sarcoma Kaposi's Sarcoma:  The Disease (Short Video) Identification of HIV as the Causative Agent in AIDS Retroviral Structure HIV Genome "The History of HIV and Current Epidemic" (video) Viral Replication Membrane Fusion Reverse Transcription Viral Replication Cycle Viral Integrase Cellular Activation Global HIV/AIDS at the Crossroads:  Where do we go from here (video) HIV Genome Organization HIV and AIDS Etiology Human T-Cell Lymphotropic Viruses (HTLV-I and HTLV-II) Transforming Retroviruses Human Immunodeficiency Viruses (HSV-1 and HIV-2 Phylogenetic Tree of the SIV and HIV viruses HIV-1 Molecular Variability Important Molecules in HIV-1 and molecular therapeutic targets (Video Lecture) Viral Transmission Sexual Transmission Transmission by Blood/Blood Products Mother to Fetal Transmission HIV Among Pregnant Women, Infants, and Children (CDC) HIV-1 Pathophysiology/Pathogenesis Initial Events in HIV Infection HIV-1 Resistance to Antibody Neutralization Long-term Infection:  Latency Phase HIV-Latency:  CD4+ T Cell Reservoir

Symptoms of HIV Disease Introduction Category C:  AIDS Surveillance Case Definition Abbreviated Guidelines for the Prevention of Opportunistic Infections in Persons Infected with HIV Pulmonary Disease PCP Pneumonia Introductory Video I (Backgound/ Biology) Introductory Video II (Prevention/Treatment) Trimethoprim/sulfamethoxazole (TMP/SMX) Bacterial Pneumonia Tuberculosis TB and HIV Co-infection (2012) video Fungal Lung Infections Cryptococcal menningitis (video) Cardiovascular Disease Cardiomyopathy Anti-HIV-Drug-Induced Myocardial Disease Combination Antiretroviral Treatment HIV Protease Inhibitors Nucleos(t)ide Reverse Transcriptase Inhibitors Effects of Anti-HIV Drugs on Blood Lipids, Glucose and Myocardial Infarction Risk HIV-Associated Electrocardiographic Abnormalities Gastrointestinal Disease Oropharyngeal Esophagitis Intestinal Effects Protozoal Infections Cryptosporidia Microsporidia Isospora belli  Cytomegaloviral colitis (CMV colitis) Algorithm for the diagnosis and management of HIV-associated diarrhea Hepatobiliary Dysfunction Gall Bladder Diseases Liver Disease Hepatitis B Hepatitis C CDC (Centers for Disease Control, USA)  fact sheet:  HIV and Viral Hepatitis Some other infectious hepatic pathogens Hepatotoxicity of Anti-Retroviral Drugs Kidney Disease HIV-Associated Nephropathy (HIVAN) Acute Kidney Injury (AKI) Electrolyte Abnormalities and Possible Causes I Electrolyte Abnormalities and Possible Causes II Antiretroviral Drugs for Treatment of Human Immunodeficiency Viral (HIV) Disease Antiretroviral Drug Classes History and Review HIV Pathogenesis Development of Antiretroviral Drugs Antiretroviral Drugs Approved in the United States Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI) table HIV Protease Inhibitor (PI) table Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI) table Enfurvirtide (Fusion Inhibitor); Maraviroc (CCR5 Inhibitor); Raltegravir (Isentress): table Nucleoside/nucleotide Reverse Transcriptase Inhibitors (Specific Drugs) Zidovudine (AZT) Stavudine (d4T, Zerit) Lamivudine (3TC, Epivir) Abacavir (Ziagen) Mutations and Abacavir Resistance Tenofovir (Viread) Emtricitabine (Emtriva) Didanosine (Videx) Zalcitabine (Hivid) Non-nucleoside Reverse Transcriptase Inhibitors Introduction Nevirapine (Viramune) Efavirenz (Sustiva) Etravirine (Intelence) Delavirdine (Rescriptor) Rilpivirine (Endurant) Integrase Strand Transfer Inhibitors (INSTI) Raltegravir (Isentress) Biomarkers (short video) Elvitegravir (Stribild,Viketa) Stribild (short video) Dolutegravir (Tivicay) Tivicay (short video) Entry Inhibitors Enfuvirtide (Fuzeon) Maraviroc (Selzentry) Protease Inhibitors (Partial Listing) Atazanavir (Reyataz) Darunavir (Prezista) Lopinavir/ritonavir (Kaletra, Aluvia) Virology Structural and Functional Review

• Viral Infections

  "Persistent Infections"¹⁴

  Attribution:  Rancaniello V Lecture #17:  Persistent Infections, https://www.youtube.com/watch?v=mrEvn3n5Y_0 Vincent Racaniello YouTube Channel:  https://www.youtube.com/channel/UCyFgCoP4ovsHbt92vM4zN2A

• Antiviral Drugs

  • Antiviral drugs may target specific steps of viral replication.³ 

    • These steps include

      • Viral binding to host cell surface receptors

      • Viral entry into the cell

      • Viral nucleic acid uncoating;

      • "Early" regulatory protein synthesis, an example being nucleic acid polymerases

      • New viral RNA or DNA synthesis

      • Synthesis of "late", structural proteins which may be used in capsid assembly

      • Viral particle assembly, the maturation step; release of active virions from the cell.³

         

        • Influenza Viral Replication Steps⁶

          Times YK "A diagram of influenza viral cell invasion and replication." 20076 http://commons.wikimedia.org/wiki/File:Virus_Replication.svg6

• Anti-Herpes Agents

  •  

    Herpes Virus Overview

    Herpesvirus belongs to the family Herpesviridae.9  Herpesviruses are classified into three subfamilies designated: alpha beta and gamma herpesvirus.9    There are nine human herpesviruses which include: 9    Herpes simplex virus11 Varicella-zoster10 Cytomegalovirus12 Epstein-Barr virus13   Diseases associated with herpesviruses include:9    Mononucleosis   Hepatitis Pneumonia Chickenpox   Encephalitis Recurrent mouth, eye and genital lesions Kaposi's sarcoma   Burkitt's lymphoma Nasopharyngeal carcinoma Serious infections in immune suppressed patients Neonatal infections Birth defects

     

  •  Herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) are responsible for a number of infections.¹ 

    • These infections result in diseases of the mouth, skin, esophagus, brain, or face in the case of HSV-1. ¹ 

    • HSV-2 infections are more commonly associated with diseases of the genitals, skin, rectum, hands or meninges.

      • HSV-1 and HSV-2 are implicated in neonatal herpes simplex virus (HSV) infections.

    • The first effective treatment for relatively less severe HSV and another herpesvirus, varicella-zoster virus (VZV) was developed over 40 years ago and approved in 1982.

    • This drug is acyclovir. ¹ 

       

      • Acyclovir (Cyclovir, Zovirax and others)

      •  Acyclovir is the prototype drug in a group of antiviral agents which must be phosphorylated intracellularly, catalyzed by both viral kinase and host cell enzymes to become the active drug which inhibits viral DNA synthesis.¹ 

        • Mechanism of Action:

        • Acyclovir:  Mechanism of Action⁵

          "In this HSV-infected human cell, the acyclovir molecules enter the cell and are converted to acyclovir monophosphate by the HSV enzyme thymiding kinase (TK).5  Enzymes in the human cell add two more phosphates to eventually form the active drug acyclovir triphosphate.5   The acyclovir triphosphate competes with 2-deoxyguanosine triphosphate (dGTP) as a substrate for viral DNA polymerase, as well as acting as a chain terminator.5   In actual infection, the HSV releases its naked capsid that delivers DNA to the human nucleus; the active drug acyclovir triphosphate exerts its action on the viral DNA located in the nucleus."5

      •  

        "Mechanism of Action of Acyclovir in Cells Infected by Herpes Simplex Virus"⁸

        "A herpes simplex virion is shown attaching to a susceptible host cell, fusing its envelope with the cell membrane, and releasing naked capsids that deliver viral DNA into the nucleus, where it initiates synthesis of viral DNA. "Acyclovir molecules entering the cell are converted to acyclovir monophosphate by virus-induced thymidine kinase. Host-cell enzymes add two more phosphates to form acyclovir triphosphate, which is transported into the nucleus. After the 3'-terminal hydroxyl of the growing herpes simplex DNA chain cleaves pyrophosphate from acyclovir triphosphate (indicated by the red arrow in the inset), viral DNA polymerase inserts acyclovir monophosphate rather than 2'-deoxyguanosine monophosphate into the viral DNA (indicated by black arrows in the inset). Further elongation of the chain is impossible because acyclovir monophosphate lacks the 3' hydroxyl group necessary forthe insertion of an additional nucleotide, and the exonuclease associated with the viral DNA polymerase cannot remove the acyclovir moiety. In contrast, ganciclovir and penciclovir have a 3' hydroxyl group; therefore, further synthesis of viral DNA is possible in the presence of these drugs. Foscarnet acts at the pyrophosphate-binding site of viral DNA polymerase and prevents cleavage of the pyrophosphate from nucleoside triphosphates, thus stalling further primer–template extension. The red bands between the viral DNA strands in the inset indicate hydrogen bonding of the base pairs." Attribution:  Slightly modified Fig. 2 from reference 8. Balfour Jr HH Antiviral Drugs in Drug Therapy (Review article Wood AJJ, ed) New England Journal of medicine 340 (16):  1255-1268 1999.

        • Acyclovir exhibits selectivity of action mainly affecting viral DNA synthesis NOT mammalian cell DNA synthesis.²  

          • This selectivity depends on acyclovir being a "prodrug" and requiring an initial phosphorylation step to acyclovir monophosphate.

            • The important point is this phosphorylation step rarely occurs in herpes-infected cells because it is catalyzed by a virus-coded thymidine kinase.

              • By contrast, very limited acyclovir phosphorylation occurs in unaffected mammalian cells acyclovir affinity for the mammalian thymidine kinase is about 200 times less than that for the viral kinase.^1,2 

                • Acyclovir triphosphate exhibits a 40-100 fold higher concentration in HSV viral infected cells compared to uninfected cells.¹

                • Host cell kinases, as described in the figure above, catalyzed multiple additional transphosphorylation steps, ultimately resulting in active drug, acyclovir triphosphate.² 

                • Acyclovir triphosphate is incorporated into viral DNA and as an analogue of 2'-3' dideoxynucleotides, causes early chain termination.²

                 

              • Acyclovir (Prodrug) Transformed into Active Drug by means of Sequential Phosphorylation Steps⁷ 

                "Rationale underlying development of acyclic nucleoside phosphonates.  Nucleoside analogues generally need to be converted by three phosphorylation steps to their 5'-triphosphate metabolites to show activity, as shown here for acyclovir (ACV)." "The first phosphorylation step, which affords the 5'-monophosphate (MP), is often the bottleneck in this transformation, and so agents could show poor activity owing to lack of transformation to the monophosphate form by nucleoside kinases." Attribution:  Figure 1A from reference 7. Figure is slightly modified by numbering phosphates.

                 

        • Anti-Herpes Simplex Viral Drugs: Principal Mechanisms of Action⁴

      • Chemistry of Acyclovir and Related Drugs

        • Acyclovir is classified as an acyclic guanine nucleoside analog which is missing a 3'-hydroxyl on the side chain.¹

          • A closely related drug, valacyclovir is a L-valyl ester prodrug for acyclovir.¹

           

        • Acyclovir (Cyclovir, Zovirax and others)

        •  

          Valacyclovir (Valtrex, Zelitrex)

References

Acosta EP Flexner C Antiviral Agents (Nonretroviral) Chapter 58 in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th edition (Brunton LL Chabner BA Knollmann BC, eds; Brunton LL, ed; Blumenthal DK  Murri N Hilal-Dandan R, assoc eds, Knollmann BC, consulting ed, on-line edition) The McGraw-Hill Companies, 2011. Baden LR Dolin R, Chapter 178, Antiviral Chemotherapy, Excluding Antiretroviral Drugs, in Harrison's Online   (Dan L. Longo, Anthony S. Fauci, Dennis L. Kasper, Stephen L. Hauser, J. Larry Jameson, Joseph Loscalzo, Eds.),  Harrison's Principles of Internal Medicine, 18th edition, The McGraw-Hill Companies, Inc. 2012. Safrin S Antiviral Agents, Chapter 49 in Basic & Clinical Pharmacology, 12 e (Katzung BG Masters SB Trevor AJ) The McGraw-Hill Companies, 2012 (on-line edition) Nath AK Thappa DM Newer trends in the management of genital herpes Indian J of Dermatology Venerology and Leprology 75(6) 561-643 November-December 2009 http://www.ijdvl.com/viewimage.asp?img=ijdvl_2009_75_6_566_57716_u1.jpg Spach DH Case2:  Acyclovir-Resistant Herpes Simplex Virus Infection; Figure 1 Acyclovir:  Mechanism of Action (Discussion section: http://depts.washington.edu/hivaids/derm/case2/discussion.html ; Case question: http://depts.washington.edu/hivaids/derm/case2/index.shtml; HSVweb Study; Case-Based Modules http://depts.washington.edu/hivaids/index.html Times YK "A diagram of influenza viral cell invasion and replication." 2007; http://commons.wikimedia.org/wiki/File:Virus_Replication.svg De Clercq E Holy A Acyclic Nucleoside Phosphonates:  A Key Class of Antiviral Drugs Nature Reviews:  Drug Discovery 4: 928-940, 2005. http://www.nature.com/nrd/journal/v4/n11/fig_tab/nrd1877_F1.html Balfour Jr HH Antiviral Drugs in Drug Therapy (Review article Wood AJJ, ed) New England Journal of medicine 340 (16):  1255-1268 1999. Roizman B Campadelli-Fiume G Longnecker R Herpesviruses Chapter 24 ( (in Acheson NH,  Fundamentals of molecular virology, 2nd edition) p. 14-16 2011, Kindle edition) Simi R Electron micrograph of a Varicella Virus http://commons.wikimedia.org/wiki/File:Varicella_(Chickenpox)_Virus_PHIL_1878_lores.jpg Wagner EK Herpes simplex virus research:  General Properties of Herpes Simplex Virus http://darwin.bio.uci.edu/~faculty/wagner/hsv2f.html Gould SE How cytomegalovirus evades the immune system Scientific American August 24, 2011 http://blogs.scientificamerican.com/lab-rat/2011/08/24/how-cytomegalovirus-evades-the-immune-system/ Smith E 50 years of Epstein-Barr virus, Part 3 Cancer Research UK http://scienceblog.cancerresearchuk.org/2014/03/26/50-years-of-epstein-barr-virus/ Rancaniello V Lecture 17 Persistent Infections https://www.youtube.com/watch?v=mrEvn3n5Y_0&feature=youtu.be (Vincent Rancaniello, Higgins Professor, Department of Microbiology & Immunology, Columbia University, New York); Virology-Biology W3310/4310, Spring 2015; Lecture 17: Persistent infections; Fling Vol II, Chapter 5); lecture pdf: http://www.virology.ws/w3310/017_W3310_15.pdf

 

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