Antiviral Agents

Question 1

What are the general mechanisms by which antivirals work?

Answer 1

Disrupt viral structure or block a virus-specific activity (enzymes, attachment, viral replication)

Question 2

Acyclovir is a common herpesvirus antiviral. What is the mechanism of action?

Answer 2

Acyclovir acts as a guanosine analog. A viral enzyme adds the first phosphate group required to activate the drug. It then competitively competes for integration into the DNA chain and terminates replication.

Question 3

What antiviral is used primarily to treat HSV?

Answer 3

Acyclovir - May also be used for Varicella, but less effective

Question 4

How have viruses developed resistance to acyclovir?

Answer 4

Loss of the gene encoding thymidine kinase (required for antiviral activation), mutation in the kinase reducing affinity for acyclovir, mutation in viral DNA polymerase that inhibits acyclovir binding

Question 5

What is Ganciclovir used to treat?

Answer 5

Generally CMV, but also used for HSV, VZV, HHV6, HHV8

Question 6

What is the mechanism of action of Ganciclovir?

Answer 6

Guanosine analog phosphorylated by a protein kinase phosphotransferase resulting in termination of chain elongation. The drug can also be phosphorylated by host enzymes.

Question 7

What CMV gene encodes a protein kinase phosphotransferase utilized to activate Ganciclovir?

Answer 7

UL97

Question 8

How have viruses developed resistance to Ganciclovir?

Answer 8

Mutations in UL97 that prevent drug phosphorylation, mutations in DNA polymerase that decrease affinity for drug

Question 9

Cidofovir is a cytidine analog. How does the antiviral differ from other nucleoside analogs?

Answer 9

The drug has the first activating phosphate attached. The second and third phosphates are added by cellular enzymes meaning the drug is present in both infected and unaffected cells

Question 10

What is the clinical usage of Cidofovir?

Answer 10

Primarily CMV in AIDS patients - Also for CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, HPV

Question 11

What is Foscarnet? What is its mechanism of action?

Answer 11

Pyrophosphate analog that binds the DNA polymerase and HIV reverse transcriptase and stops DNA synthesis

Question 12

What is the clinical usage of Foscarnet?

Answer 12

Ganciclovir-resistant CMV, acyclovir-resistance HSV or VZV

Question 13

Some anti-HBV drugs manipulate the immune response. How is this possible?

Answer 13

The drug binds and activates interferon receptors on hepatocytes, activating expression of IF-stimulated genes. These also increase MHC-I expression on affected cells.

Question 14

Tenofovir and Entecavir are FDA-approved anti-HBV drugs. How do they work?

Answer 14

Tenofovir is an adenine analog that targets the reverse transcriptase and does not need phosphorylation for activation.

Entecavir is a deoxyguanosine analog that must be phosphorylated for activation.

Question 15

How does HCV therapy differ from that of HBV?

Answer 15

HBV therapy is meant to manage the virus. HCV anti-virals are intended to eradicate the virus and maintain undetectable levels.

Question 16

What are the 5 classes of anti-retroviral drugs?

Answer 16

Attachment/Entry Inhibitors, Nucleoside Reverse Transcriptase Inhibitors (NRTIs), Non-Nuecloside Reverse Transcriptase Inhibitors (NNRTIs), Integrase Strand Transfer Inhibitors (INSTIs), Protease Inhibitors

Question 17

Temsavir is an anti-retroviral entry inhibitor. What is the mechanism of action?

Answer 17

Binds to hp120 and prevents attachment to the CD4 receptor

Question 18

Ibalizumab is a monoclonal antibody for ART. What is the mechanism of action?

Answer 18

Binds to CD4a, preventing the required conformation change when gp120 binds the receptor

Question 19

Maraviroc is an anti-retroviral entry inhibitor. How does it work?

Answer 19

Binds CCR5 and alters the conformation to prevent HIV binding. The drug is ineffective against CXCR4 viruses and may lead to selection for viruses that bind X4.

Question 20

How is HIV fusion with the host cell inhibited?

Answer 20

Enfuvirtidae binds to gp41. This blocks the conformational change that occurs after gp120 binds CD4 and prevents gp41 from mediating fusion.

Question 21

Nucleoside reverse transcriptase inhibitors (NRTIs) are used as the first ART for HIV. How does the drug work?

Answer 21

Nueclosides requires phosphorylation for action and then bind the reverse transcriptase and terminate chain elongation

Question 22

How does the mechanism of Non-nucleoside reverse transcriptase inhibitors differ from nucleoside reverse transcriptase inhibitors for ART?

Answer 22

Non-nucleoside reverse transcriptase inhibitors target the reverse transcriptase, but bind at a site distinct from the active sight and inhibit binding of new nucleotides. The drug does not act as a nuceloside and does not need to be phosphorylated for activation. Resistance is distinct from that against NRTIs.

Question 23

What is the mechanism of integrase strand transfer inhibitors?

Answer 23

Bind to Mg2+ to inhibit binding of the preintegration complex to host DNA. This blocks the DNA provirus from being integrated into host DNA. Resistance is uncommon.

Question 24

What is the mechanism of ART protease inhibitors?

Answer 24

Bind the enzymatic pocket of the HIV protease and inhibit function. This prevents maturation of the virus to an infectious particle. This ART is used for patients failing other regiments as resistance is uncommon.

Question 25

What side effects may be seen from use of protease inhibitors and NNRTIs?

Answer 25

Lipoatrophy (fat wasting) & hyperadiposity (fat accumulation)

Question 26

Ribavirin is used to treat RSV, but is active against both DNA & RNA viruses. What is the mechanism of action?

Answer 26

A guanosine analog that is phosphorylated and activated by host enzymes. The drug inhibits the RNA-dependent RNA polymerase to induce excess mutations. It also inhibits the host inosine monophosphate dehydrogenase resulting in low GTP.

Question 27

How is RSV prevented with prophylaxis?

Answer 27

Palazuvimad Used in high risk pediatric patients, monoclonal antibodies bind epitope on the F protein and act as neutralizing antibodies

Question 28

There are three classes of anti-influenza drugs. What are the mechanisms of action for each?

Answer 28

Adamantanes - inhibit M2 ion channel and interfere with uncoating. No longer used

Neuraminidase Inhibitors - Block viral neuraminidase function and prevent viral release

Baloxavir marboxil - Inhibits the cap-dependent endonuclease of the RNA polymerase

Question 29

Direct-acting antivirals are used for HCV treatment. What are they and what are their targets?

Answer 29

Protease inhibitors - Target NS3/NS4A that form the viral protease

Nucleoside/nucleotide analogs - Inhibit NS5B and cause chain termination

NS5A inhibitors - Inhibit RNA replication and viral assembly

Question 30

What classes of anti-viral medications are used in patients with mild to moderate COVID at risk for sever illness?

Answer 30

Protease inhibitor & Cytochrome P450 3A4 inhibitor

Question 31

Remdesivir is used to treat COVID. What is the mechanism of action?

Answer 31

Adenosine analog that is phosphorylated and stalls the RNA dependent RNA protease resulting in chain termination

Question 32

What is the mechanism of action of COVID monoclonal antibodies?

Answer 32

Binds to spike proteins to neutralize the virus

Question 33

What is the mechanism of action of prodrug NHC to treat COVID?

Answer 33

NHC is metabolized to the triphosphate form and incorporated into the RNA strand. NHC-TP binds with C or A, leading to mutations, and non-replicative virion