Antiviral Drugs

Question 1

Where in the viral lifecycle does ACYCLOVIR work?

Answer 1

Nucleic Acid Synthesis Inhibitor for Herpes Viruses

Question 2

EFAVIRENZ and NEVIRAPINE are what type of drugs?

Answer 2

NNRTIs, nucleic acid synthesis inhibitors

Have VIR in the middle of the name.

Question 3

The HIV retrovirus attacks what kind of cells?

Answer 3

CD4+ T-cells

Question 4

MOA of ENFIRVITIDE?

Answer 4

Prevents fusion of the viral membrane with the host cell membrane.

By mimicking HRI and binding HR2, it prevents the formation of a pore.

Question 5

Name the 2 antivirals that inhibit retroviral entry into the host cell.

Answer 5

ENFIRVITIDE and MARAVIROC

“TIDE is coming in. Cell membrane better be like a ROC.”

Question 6

What is unique about the MOA of MARAVIROC?

Answer 6

MARAVIROC antagonizes the HOST CELL’s CCR5 Receptor. No other antiviral targets the host cell.

Blocks HIV strains that utilize the CCR5 chemokine receptor to bind to the host cell and fuse.

Question 7

How could a virus easily develop resistance to MARAVIROC?

Answer 7

TROPISM: HIV viruses could use a different chemokine receptor to bind to the host cell membrane.

Question 8

Describe the replication cycle of a retrovirus.

Answer 8

1) Attachment
2) Fusion via gp41 and gp120 proteins interacting with host cell CCR5 and CD4 receptors
3) Uncoating
4) Reverse Transcription of ssRNA (via reverse transcriptase)
5) Integration into the host cell genome (integrase)
6) Transcription/Translation by host cell enzymes
7) Assembly
8) Proteolytic cleavage = maturation –> Budding.

Question 9

Why can’t you target transcription and translation processes in a retrovirus?

Answer 9

Because HIV hijacks the host cell’s machinery and uses it for transcription and translation.

Question 10

Currently approved HIV drugs target which of the replication cycle processes?

Answer 10

Fusion - ENFIRVITIDE and MARAVIROC

Reverse Transcription (Reverse transcriptase)

Integration (Integrase enzyme)

Maturation (viral proteases)

Question 11

Most of the drugs that block viral nucleic acid synthesis are nucleoside analogs. What is a nucleoside analog?

Answer 11

Artificial nucleosides that get incorporated into the replicating DNA, terminating its growth. THey compete with endogenous nucleotides for incorporation into the growing viral DNA strand.

Question 12

What is an NRTI? What about NNRTI? What is the main difference between the two nucleic acid synthesis inhibitors?

Answer 12

NRTI= Nucleoside reverse transcriptase inhibitors.

NNRTI= non-nucleoside reverse transcriptase inhibitors.

NRTIs must be activated by host cell kinases before it is active. (-PPP form) (Converted to triphosphate nucleotides)

Question 13

ABACAVIR
LAMIVUDINE 
TENOFOVIR DISOPROXIL, 
ZIDOVUDINE, 
and EMTRICITABINE are what kind of drugs? 

MOA?

Answer 13

NRTIs. - they are nucleoside analogs that compete with endogenous nucleotides for incorporation onto viral DNA. Once added to the elongating chain, it is terminated, inhibiting viral replication.

Mnemonic: LATEZ. Go to starbucks for LATEZ.

Question 14

NNRTIs (directly/indirectly) target reverse transcriptase, while NRTIs (directly/indirectly) target it.

Answer 14

NNRTIs DIRECTLY target reverse transcriptase by binding to a hydrophobic pocket directly on the enzyme.

NRTIs INDIRECTLY target reverse transcriptase by messing up its function through incorporation of dysfunctional nucleotides.

Question 15

Describe the primary mechanism of toxicity involving NRTIs.

Answer 15

NRTIs not only inhibit reverse transcriptase, but the host cell’s MITOCHONDRIAL polymerase as well. This leads to decreased protein synthesis in the mitochondria, leading to decreased oxidative phosphorylation and lower ATP production as a result.

Refer to pathology for what happens to a cell when ATP production is low.

Question 16

Do NRTIs convey evidence of cross-resistance? What is the virus’s mechanism of resistance against NRTIs?

Answer 16

YES there is cross resistance.

This resistance occurs through mutations at reverse transcriptase codons, altering the enzyme.

Question 17

Name the 2 NNRTIs.

Answer 17

EFAVIRENZ and NEVIRAPINE

Question 18

What is the mechanism of ACYCLOVIR and GANCICLOVIR?

Answer 18

NOT AN HIV drug, but is a NUCLEIC ACID SYNTHESIS INHIBITOR.

ACYCLOVIR and GANCICLOVIR are nucleoside analogs, converted to triphosphate form by host cell kinases before incorporation into the growing DNA strand. Once the Viral DNA Polymerase adds it, it gets stuck and rendered useless.

Question 19

What is the MOA of Valacyclovir and Valganciclovir?

Answer 19

They work the same way as ACYCLOVIR and GANCICLOVIR, but they are orally-absorbed pro-drugs that rapidly become active when they enter circulation.

Question 20

EFAVIRENZ and NEVIRAPINE are in what class of drugs?

Answer 20

HIV Nucleic Acid Synthesis Inhibitors.

Specifically are NNRTIs.

Question 21

EFAVIRENZ and NEVIRAPINE are effective only against one strain of HIV. Name the strain. Describe why this is.

Answer 21

HIV-1 - has a strain-specific binding site target on the HIV-1 reverse transcriptase.

Question 22

WHy should you not give an HIV-1 patient and NRTI and an NNRTI simultaneously?

Answer 22

NNRTIs are noncompetitive inhibitors of NRTIs. You’d have the efficacy of 1 drug (NNRTI) and the toxicity of both.

Question 23

Describe the MOA of NNRTIs.

Answer 23

Bind to a hydrophobic pocket in the p66 subunit of the HIV-1 reverse transcriptase enzyme. Binding alters the conformation of the enzyme and impedes the activity. No more viral replication.

Question 24

Why is it easy for a virus to develop NNRTI resistance?

Answer 24

A single point mutation in the hydrophobic pocket of the enzyme would cause resistance.

Question 25

What enzyme does RALTEGRAVIR inhibit? in which HIV strains?

Answer 25

INTEGRASE of HIV-1 and HIV-2

Question 26

ATAZANAVIR and RITONAVIR block what aspect of the HIV replication cycle?

Answer 26

“Maturation” according to Sweatman, which is the cleavage of the translated viral polypeptide into functional, mature viral proteins.

They are HIV-1 PROTEASE INHIBITORS

Question 27

What HIV Protease inhibitor is also a major CYP34A inhibitor? Why is this beneficial to prescribe in conjucntion with another HIV drug?

Answer 27

RITONAVIR

Since RITONAVIR inhibits CYP34A as well as the viral protease, it prolongs the active serum concentration of the other simultaneously prescribed drug.

Question 28

What is the target of HIV Protease Inhibitors? (Specific enzyme name)

Answer 28

Aspartyl Protease

Question 29

Name the 4 steps in the HIV cycle targeted by drugs and the drugs that inhibit them.

Answer 29

1) Fusion with host cell: ENFURVITIDE and MARAVIROC

2) Reverse Transcription: LATEZ
LAMIVUDINE
ABACAVIR
TENOFOVIR DISOPROXIL
EMTRICITABINE
ZIDOVUDINE

3) Integration : RALTEGRAVIR
4) Maturation: ATAZANAVIR, RITONAVIR

Question 30

What do BECEPRAVIR and TELEPRAVIR do? What virus do they work on? MOA?

Answer 30

Hepatitis C Protease inhibitors.

They antagonize SERINE PROTEASE so it can’t cleave the translated viral polypeptide into its functional subunits.

Question 31

What is the easy way for a virus to develop resistance against BOCEPRAVIR and TELEPRAVIR?

Answer 31

Serine protease mutations.

Question 32

Describe the INFLUENZA pathway of fusion/uncoating. (complicated…)

Answer 32

Flu endures the host via receptor-mediated endocytosis and is contained within an early endosome.

A H+ATPase pumps H+ ions into the endosome, lowering the pH and inducing a pH-dependent conformational change in the viral envelope.
Hemagglutinin (HA) protein triggers viral/endosomal envelope fusion.

This alone isn’t enough to trigger uncoating though. A pH gated proton channel in the viral membrane (M2) opens, releasing RNP from the viral matrix (ribonucleoprotein) and releasing the viral genetic material into the host cell.

Question 33

What is the MOA of AMANTADINE and RIMANTIDINE?

Answer 33

Block the M2 proton channel of the flu viral membrane. No release of genetic material into the host cytoplasm.

Amantadine sounds like Adamantium (X-men)

Question 34

What is the MOA of PEGINTERFERON?

Answer 34

Multiple mechanisms.

PEGINTERFERON is just a long-lasting formula of interferon (IFN) conjugated with polyethylene glycol for longevity.

IFN binding to host cell surface receptors triggers the formation of many antiviral proteins.

Question 35

PEGINTERFERON is not widely used anymore due to adverse effects. What virus is it still used to combat?

Answer 35

Hep C

Question 36

What role do neuramidases play in the flu viral life cycle?

Answer 36

Neuramidases help the flu virus bud off from the host cell.

They cleave the terminal sialic acid residues from the host cell membrane surface.

Question 37

What is the MOA of ZANAMIVIR, OSELTMIVIR?

Answer 37

Inhibit viral release.

Sialic acid analogues that bind to flu viral neuramidase enzymes, preventing them from cleaving the terminal sialic acid residues.

Prevents the budding of the new flu viruses. They get caught on the host cell’s sialic acids!

Question 38

T/F: Drug therapy causes mutations.

Answer 38

DRUG THERAPY DOES NOT CAUSE MUTATIONS.

It provides selective pressure to promote the growth of naturally occurring mutant

Question 39

3 things cause failure of HIV drug regimens: Name them.

Answer 39

1) Patient non-compliance in taking the drugs
2) Resistance
3) They can’t stop having unprotected sex and they get a new strain.

Question 40

What does FOSCARNET do?

Answer 40

Inhibit DNA polymerase in Flu virus

Question 41

Considering the process of HIV attachments, entry, replication, and release, put the following drugs in the correct sequence:
Atazanavir
Efavirenz
Enfurvitide
Raltegravir

Answer 41

Enfurvitide - prevents fusion (mimics HR1)
Efavirenz - NNRTI
Raltegravir - Intgration
Atazanavir - Protease inhibitor.

Question 42

Both primary and secondary mutations occur against protease inhibitors. What is the significance of this?

Answer 42

Primary mutations only have a small effect on resistance. Additional (secondary) mutations that occur with continued use of protease inhibitors brings about high levels of resistance.