Pharmacology: Antifungal and Antiviral Agents
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Questions and Answers

What is a distinct feature of NtRTIs when compared to NRTIs?

  • Presence of a phosphonate group that is isosteric with the phosphate group of normal nucleotides (correct)
  • Ability to bind to the active site of HIV-1 reverse transcriptase
  • Lack of a phosphonate group
  • Requirement for a hydrophobic pocket for binding

    • What is the mechanism of action of NNRTIs?

  • Competitive inhibition of HIV-1 reverse transcriptase
  • Uncompetitive inhibition of HIV-1 integrase
  • Allosteric inhibition of HIV-1 reverse transcriptase (correct)
  • Non-competitive inhibition of HIV-1 protease

    • What is the primary reason why NNRTIs are not used as monotherapy?

  • Limited bioavailability
  • Severe side effects
  • High toxicity
  • Rapid development of resistance (correct)

    • What is the characteristic structure of NNRTIs?

    <p>Butterfly structure with a hydrophilic body and two hydrophobic wings</p> Signup and view all the answers

    What are the two main amino acids involved in the binding site of NNRTIs?

    <p>Lys101 and Lys103</p> Signup and view all the answers

    Which of the following is NOT an NNRTI?

    <p>Adefovir</p> Signup and view all the answers

    What is the function of HIV protease inhibitors?

    <p>To competitively inhibit the action of the virus aspartyl protease</p> Signup and view all the answers

    What is the preferred cleavage site for the HIV protease enzyme?

    <p>The N-terminal side of proline residues, especially between phenylalanine and proline</p> Signup and view all the answers

    What is the common feature of all licensed protease inhibitors (PIs) for clinical use, except for tipranavir?

    <p>They are built upon the hydroxyethylene scaffold [CH(OH)-CH2]</p> Signup and view all the answers

    What is the crucial component involved in the reaction mechanism of HIV protease inhibitors?

    <p>Asp-25 and Asp-25’</p> Signup and view all the answers

    What is the nucleophile involved in the reaction mechanism of HIV protease inhibitors?

    <p>Water molecule</p> Signup and view all the answers

    What is the rationale behind designing HIV protease inhibitors based on the enzyme’s natural peptide substrates?

    <p>To allow a good binding interaction between the substrate and the enzyme</p> Signup and view all the answers

    What is the consequence of designing PIs with a high molecular weight?

    <p>Poor oral bioavailability</p> Signup and view all the answers

    What is the specific mechanism of action of Maraviroc?

    <p>Blocking protein-protein interactions between gp120 and CCR5</p> Signup and view all the answers

    What is the primary function of Enfuvirtide?

    <p>Inhibiting the fusion of HIV-1 and host cell</p> Signup and view all the answers

    What is the outcome of gp41 helices folding over each other?

    <p>Enhancing the fusion of HIV-1 and host cell</p> Signup and view all the answers

    What is the characteristic of Enfuvirtide?

    <p>A polypeptide containing 36 amino acids</p> Signup and view all the answers

    What is the year Enfuvirtide was first used against HIV?

    <p>2003</p> Signup and view all the answers

    What is the consequence of losing one H-bond interaction at C-2?

    <p>No energy penalty involved in distorting from chair conformation</p> Signup and view all the answers

    What is the mode of action of ribavirin?

    <p>Inhibition of viral messenger RNA synthesis</p> Signup and view all the answers

    What is the characteristic of interferons?

    <p>They are potent cytokines with antiviral and immunomodulating activities</p> Signup and view all the answers

    What is the consequence of using neuraminidase inhibitors such as oseltamivir?

    <p>Development of resistance against neuraminidase inhibitors</p> Signup and view all the answers

    What is the mechanism of action of zanamivir?

    <p>Trapping newly formed virions and inhibiting viral replication</p> Signup and view all the answers

    What is the characteristic of adefovir?

    <p>It is a purine nucleoside analogue with a modified base and D-ribose sugar</p> Signup and view all the answers

    What is the mechanism of action of Dasabuvir?

    <p>Binds to the palm domain of NS5B and induces a conformational change</p> Signup and view all the answers

    What is unique about Sofosbuvir?

    <p>It has a high barrier to HCV resistance development</p> Signup and view all the answers

    What is the target of Tecovirimat?

    <p>The viral p37 protein</p> Signup and view all the answers

    What is the effect of Imiquimod on the immune system?

    <p>It induces cytokines and chemokines with antiviral effects</p> Signup and view all the answers

    What is the result of Tecovirimat's disruption of p37's cellular localization?

    <p>Prevention of viral envelope formation</p> Signup and view all the answers

    What is the effect of Imiquimod on genital warts?

    <p>It induces a local immune response and reduces viral load and wart size</p> Signup and view all the answers

    Study Notes

    Antiviral Agents

    • High molecular weight of PIs leads to poor oral bioavailability
    • Most PIs are designed to have a core unit spanning the S1 to S1′ subsites, with additional substituents to fit into the S2/S3 and S2′/S3′ subsites

    Entry Inhibitors

    • Maraviroc (Selzentry) is a CCR5 antagonist, approved in 2007, and works by blocking protein-protein interactions between gp120 and CCR5
    • Maraviroc selectively binds to the human chemokine receptor CCR5 present on the membrane of CD4 cells (T-cells), preventing the interaction of HIV-1 gp120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells

    Fusion Inhibitors

    • Enfuvirtide is a polypeptide containing 36 amino acids, used to treat HIV since 2003
    • Enfuvirtide acts as a fusion inhibitor by binding to gp41 and preventing the folding of the helices, which draws the virus and host cell together leading to fusion

    Nucleotide Reverse Transcriptase Inhibitors (NtRTIs)

    • NtRTIs contain a phosphonate group that is isosteric with the phosphate group of normal nucleotides
    • Examples of NtRTIs include adefovir and tenofovir, used to treat HBV and HIV infections, respectively

    Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

    • NNRTIs bind to a hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase, inducing a conformational change that disrupts catalytic activity
    • Examples of NNRTIs include nevirapine, etravirine, and rilpivirine
    • NNRTIs are noncompetitive inhibitors that bind to a site on the HIV-1 reverse transcriptase that is distant from the active site, making them prone to rapid resistance development

    HIV Protease Inhibitors

    • HIV protease inhibitors are peptide-like chemicals that competitively inhibit the action of the virus aspartyl protease
    • The preferred cleavage site for this enzyme is the N-terminal side of proline residues, especially between phenylalanine and proline
    • HIV protease inhibitors prevent the metamorphosis of HIV virus particles into their mature infectious form

    Neuraminidase Inhibitors

    • Neuraminidase inhibitors trap the newly formed virions, working on cap-dependent endonucleases and by metal chelation
    • Examples of neuraminidase inhibitors include zanamivir
    • Influenza A readily develops resistance against neuraminidase inhibitors such as oseltamivir

    Anti-Hepatitis C Agents

    • Adefovir is used to treat HBV and HIV infections
    • Ribavirin is a purine nucleoside analogue that alters cellular nucleotide pools and inhibits viral messenger RNA synthesis
    • Interferons are potent cytokines that possess antiviral, immunomodulating, and antiproliferative activities
    • Sofosbuvir is a nucleotide analog that exhibits a high barrier to HCV resistance development

    Antivariola Virus Agent

    • Tecovirimat is the only approved treatment for pox virus and is effective against vaccinia, monkeypox, and cowpox as well as variola
    • Tecovirimat targets the viral p37 protein, disrupting the cellular localization of p37 and preventing its association with cellular protein involved in membrane trafficking

    Other Agents

    • Imiquimod (Aldara) is a novel immunomodulatory agent that induces cytokines and chemokines with antiviral and immunomodulating effects

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    Description

    This quiz covers nucleotide reverse transcriptase inhibitors (NtRTIs) used in the treatment of Hepatitis B and HIV infections, including adefovir and tenofovir.

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