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?

Butterfly structure with a hydrophilic body and two hydrophobic wings Signup and view all the answers

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

Lys101 and Lys103 Signup and view all the answers

Which of the following is NOT an NNRTI?

Adefovir Signup and view all the answers

What is the function of HIV protease inhibitors?

To competitively inhibit the action of the virus aspartyl protease Signup and view all the answers

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

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

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

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

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

Asp-25 and Asp-25’ Signup and view all the answers

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

Water molecule Signup and view all the answers

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

To allow a good binding interaction between the substrate and the enzyme Signup and view all the answers

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

Poor oral bioavailability Signup and view all the answers

What is the specific mechanism of action of Maraviroc?

Blocking protein-protein interactions between gp120 and CCR5 Signup and view all the answers

What is the primary function of Enfuvirtide?

Inhibiting the fusion of HIV-1 and host cell Signup and view all the answers

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

Enhancing the fusion of HIV-1 and host cell Signup and view all the answers

What is the characteristic of Enfuvirtide?

A polypeptide containing 36 amino acids Signup and view all the answers

What is the year Enfuvirtide was first used against HIV?

2003 Signup and view all the answers

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

No energy penalty involved in distorting from chair conformation Signup and view all the answers

What is the mode of action of ribavirin?

Inhibition of viral messenger RNA synthesis Signup and view all the answers

What is the characteristic of interferons?

They are potent cytokines with antiviral and immunomodulating activities Signup and view all the answers

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

Development of resistance against neuraminidase inhibitors Signup and view all the answers

What is the mechanism of action of zanamivir?

Trapping newly formed virions and inhibiting viral replication Signup and view all the answers

What is the characteristic of adefovir?

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

What is the mechanism of action of Dasabuvir?

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

What is unique about Sofosbuvir?

It has a high barrier to HCV resistance development Signup and view all the answers

What is the target of Tecovirimat?

The viral p37 protein Signup and view all the answers

What is the effect of Imiquimod on the immune system?

It induces cytokines and chemokines with antiviral effects Signup and view all the answers

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

Prevention of viral envelope formation Signup and view all the answers

What is the effect of Imiquimod on genital warts?

It induces a local immune response and reduces viral load and wart size 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.