Pharmacology: Antifungal and Antiviral Agents

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

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