Pharm: Anti-Viral Mechanisms

Question 1

Most antivirals are active against ____ viruses, whereas most antibacterial drugs target ____ bacterial species.

Answer 1

only one or a few viruses; multiple bacterial species

Question 2

Maraviroc and Enfuvirtide are two drugs that act to inhibit what part of the virus replication cycle?

Answer 2

Attachment and entry

Question 3

Amantadine and Rimantadine (Adamantane class drugs) are two drugs that act to block ____ to inhibit the ____ step of the virus replication cycle.

Answer 3

the action of the viral M2 ion channel protein; uncoating

Question 4

Acyclovir, Zidovudine, and Efavirenz are ____ inhibitors that act to prevent ____ in the viral replication cycle.

Answer 4

polymerAZE inhibitors; genome replication

Question 5

Raltegravir is an inhibitor of ____ that acts to prevent ____ in the viral replication cycle.

Answer 5

inhibitor of integrase; genome replication

Question 6

Saquinavir and Ritonavir are ____ inhibitors that act to prevent ____ in the viral replication cycle.

Answer 6

protease inhibitors; assembly and maturation

Question 7

Zanamivir and Oseltamivir are ____ inhibitors that act to prevent ____ in the viral replication cycle.

Answer 7

neuraminidase inhibitors; egress and release

Question 8

Many of the currently approved antiviral
agents are ____ analogues that target genome
replication, typically by inhibiting ____ or reverse transcriptase.

Answer 8

nucleoside; viral DNA polymerase

Question 9

The HIV virus infects ____ cells.

Answer 9

CD4+

Question 10

For the HIV virus, the stage of virus attachment is dependent on binding interactions between viral ____ and ____ proteins and host cell CD4 and certain chemokine receptors.

Answer 10

gp41 and gp120 proteins

Question 11

What stage of virus attachment allows the HIV genome to enter the host cell?

Answer 11

fusion - of the viral membrane (envelope) with the host cell plasma membrane

Question 12

Uncoating permits the ssRNA HIV genome to be copied by ____ ____ into dsDNA.

Answer 12

reverse transcriptase

Question 13

What reaction depends on HIV-encoded integrase?

Answer 13

integration of HIV DNA into the host cell genome

Question 14

Is viral gene transcription and post-transcriptional processing to produce genomic HIV RNA and viral mRNA performed by viral or host cell enzymes?

Answer 14

host cell enzymes carry out viral gene transcription and post-transcriptional processing

Question 15

Viral HIV mRNA is translated into proteins on what machinery?

Answer 15

host cell ribosomes

Question 16

True or false: HIV virions are fully mature when they bud from the infected host cell.

Answer 16

False - they will undergo proteolytic cleavage which will mature them into fully infective virions

Question 17

The method of influenza A entry into a cell involves binding of ____ protein to ____ ____ receptors on the host cell surface, and the virus enters the cell by ____-____ endocytosis.

Answer 17

hemagglutinin; sialylated glycoprotein; receptor-mediated endocytosis

Question 18

Internalization and endosomal acidification of influenza A virus permits fusion of ____ by altering the conformation of ____.

Answer 18

fusion of host and viral membranes (within the endosome); altering hemagglutinin

Question 19

In the nucleus of infected cells, the influenza A viral RNAs are transcribed into mRNAs, and replicated by what enzyme?

Answer 19

viral RNA-dependent RNA polymerase

Question 20

The drug Enfuvirtide is used in the treatment of what virus, and what does it inhibit?

Answer 20

treat HIV; it mimics HR2, binds to HR1, and prevents the HR2– HR1 interaction thereby trapping the virus at the attachment stage and preventing entry into the host cell

Question 21

The drug Maraviroc is used in the treatment of what virus, and what does it inhibit?

Answer 21

treat HIV; it’s an antagonist of the CCR5 chemokine receptor and blocks cellular infection of HIV strains that use CCR5 for attachment and entry

Question 22

The drug amantadine is used in the treatment of what virus, and what does it inhibit?

Answer 22

treat influenza; it inhibits the M2 (pH-gated) proton channel located in the viral envelope. Protons must enter the virion (via M2) in order to dissociate matrix protein from RNP and allow the RNPs to be released into host cell cytoplasm

Question 23

The drug rimantadine is used in the treatment of what virus, and what does it inhibit?

Answer 23

treat influenza; it inhibits the M2 (pH-gated) proton channel located in the viral envelope. Protons must enter the virion (via M2) in order to dissociate matrix protein from RNP and allow the RNPs to be released into host cell cytoplasm

Question 24

In the HIV virus: the binding of glycoprotein gp120 to a host cell receptor–such as a ____ receptor–causes a conformational change in ____ which exposes the fusion peptide ____ and ____. The fusion peptide then ____ into the host cell membrane.

Answer 24

CD4 and certain chemokine receptors; gp41; HR1 and HR2 (heptad-repeat region); inserts

Question 25

In the infection of influenza virus: what triggers fusion of the viral envelope with the endosomal membrane?

Answer 25

low pH, or acidification of the endosome by proton pumps (the normal process of endosomes)

Question 26

Drugs acting against polymerases to inhibit replication of viral genomes belong to 2 classes. What are they?

Answer 26

nucleoside inhibitors and non-nucleoside inhibitors

Question 27

Nucleoside analogues require ____ ____ before incorporation of the deoxyribonucleoside triphosphate into the growing DNA chain. *This takes the form of ____ ____ by ____.

Answer 27

metabolic activation; intracellular phosphorylation by kinases

Question 28

Nucleoside analogues are used primarily in the treatment of what 2 infections?

Answer 28

herpes and HIV

Question 29

Incorporation of nucleoside analogues (such as in the case of treatment with acyclovir and ganciclovir) leads to what?

Answer 29

termination of DNA chain elongation

Question 30

True or false: valacyclovir and valganciclovir are orally absorbed in their bioactive form.

Answer 30

False - they are orally absorbed pro-drugs that rapidly liberate the respective active drug (acyclovir and ganciclovir) upon entry into the circulation

Question 31

The activated triphosphate form of both acyclovir and ganciclovir (pppACV and pppGCV) act as competitive inhibitors of ____ binding.

Answer 31

Deoxyguanosine triphosphate (dGTP) aka pppdG

Question 32

What does "NRTI" stand for? | What function do they inhibit and how?

Answer 32

"nucleoside reverse transcriptase inhibitors"; inhibit the action of reverse transcriptase, a DNA polymerase that can copy both DNA and RNA, by competing with endogenous nucleosides for incorporation into viral DNA; they cause termination once incorporated

Question 33

What are NNRTIs and how are they different from NRTIs?

Answer 33

non-nucleoside reverse transcriptase inhibitors; they bind a hydrophobic pocket in the p66 subunit of the HIV reverse transcriptase; they are non-competitive inhibitors with NRTIs and they are specific for HIV reverse transcriptase

Question 34

What is a Thymidine analogue mutation?

Answer 34

mutations at reverse transcriptase codons that confer cross-resistance to thymidine analogues and NRTIs

Question 35

Efavirenz and Nevirapine are what type of reverse transcriptase inhibitors? How do they exert their effect?

Answer 35

non-nucleoside reverse transcriptase inhibitors (NNRTIs); they bind the reverse transcriptase and alter the 3D structure thereby impeding its activity

Question 36

True or false: NNRTIs require intracellular phosphorylation before they can exert their inhibitor effect.

Answer 36

False - they require no phosphorylation (unlike the NRTIs) because they just have to bind the transcriptase

Question 37

True or False: the binding site for NNRTIs is virus-strain specific.

Answer 37

True

Question 38

Adefovir is converted to ____ form and serves as a competitive inhibitor of viral DNA polymerases/reverse transcriptase with respect to ____ ____.

Answer 38

diphosphate form; deoxyadenosine triphosphate | *Aid: ADEfovir and ADEnosine

Question 39

True or False: Adefovir has a higher affinity for cellular polymerases than for HBV DNA polymerase.

Answer 39

False - Adefovir has a higher affinity for HBV DNA polymerase

Question 40

Entecavir is converted to ____ form and serves as a competitive inhibitor of ___ DNA polymerase with respect to ____ ____.

Answer 40

triphosphate form; HBV; deoxyguanosine triphosphate

Question 41

Is Entecavir a weak or strong inhibitor of cellular DNA and mitochondrial polymerases?

Answer 41

weak inhibitor

Question 42

Lamivudine is converted to ____ form and serves as a competitive inhibitor of ____ DNA polymerase.

Answer 42

triphosphate form; HBV

Question 43

Telbivudine is converted to ____ form and serves as a competitive inhibitor of ___ DNA polymerase with respect to ____ ____.

Answer 43

triphosphate; HBV; thymidine 5"-triphosphate

Question 44

How much toxicity does Telbivudine have towards human cellular DNA polymerases?

Answer 44

little toxicity

Question 45

Ribavirin is converted to ____ form and serves as a competitive inhibitor of _________ and specifically _________ activity.

Answer 45

triphosphate; GTP-dependent 5'-capping of viral mRNA; influenza virus transcriptase

Question 46

Trifluridine irreversibly inhibits ____ ____ and specific DNA polymerases, thereby inhibiting ____ ____.

Answer 46

thymidylate synthase; DNA synthesis

Question 47

How likely is viral resistance to Trifluridine?

Answer 47

rare

Question 48

Raltegravir blocks catalytic activity of what?

Answer 48

HIV-1 and -2-encoded integrase; thereby prevents integration of viral DNA into host chromosome

Question 49

How can a virus become resistant to Raltegravir?

Answer 49

primary mutations in the integrase gene

Question 50

HIV-1 protease inhibitors are specific inhibitors of the viral ____ ____ enzyme that is responsible for proteolytic cleavage of precursor polypeptides.

Answer 50

aspartyl protease

Question 51

Preventing cleavage of HIV gag and pol precursor polypeptides prevents what?

Answer 51

metamorphosis of HIV particles into their mature infectious form

Question 52

Atazanavir, Ritonavir, amprenavir, indinavir, lopinavir, nelfinavir, and saquinavir are all what type of drugs?

Answer 52

HIV-1 protease inhibitors | *Aid: recognize names by common suffix: "vowel-navir"

Question 53

Bocepravir and Telaprevir have gained recent approval for the treatment of what virus?

Answer 53

Hepatitis C - by blocking the formation of several critical non-structural proteins

Question 54

What do the enzymes signal peptidase, NS2/3 protease, and NS3/4A serine protease do?

Answer 54

they cleave the polyprotein that is created by the translation of the HCV RNA upon infection in a host into 10 proteins

Question 55

Peginterferon is a long-lasting formula of ____ that is conjugated with ____ ____.

Answer 55

interferon; polyethylene glycol

Question 56

The binding of IFN to specific cell surface receptor molecules signals the cell to do what?

Answer 56

produce a series of antiviral proteins to interfere with viral transcription, translation, post-translational processing, virus maturation, and virus release

Question 57

How do the effects of interferon inhibit viral RNA transcription?

Answer 57

activates Mx protein, blocks viral RNA synthesis | *Mx=cellular protein with anti-viral activity, induced by IFN-binding

Question 58

How do the effects of interferon inhibit viral RNA translation?

Answer 58

activates methylase, 2'5' oligioadenylate synthetase, PK1, and PDE

Question 59

How do the effects of interferon inhibit viral RNA post-translational processing?

Answer 59

inhibits glycosyltransferase, thereby reducing protein glycosylation

Question 60

How do the effects of interferon inhibit virus maturation?

Answer 60

inhibits glycosyltransferase, thereby preventing glycoprotein maturation

Question 61

How do the effects of interferon inhibit virus release?

Answer 61

causes membrane changes that blocks virus budding

Question 62

Zanamivir and Oseltamivir are potent and selective ____ ____ analogue inhibitors that induce conformational changes in the active site of ____ ____ which inhibits them.

Answer 62

sialic acid; influenza-A and -B neuraminidases

Question 63

Neuraminidases are viral enzymes that are essential for destruction of terminal sialic acid residues. What consequence does this have?

Answer 63

destruction of sialic acid residues destroys the receptors recognized by viral hemagglutinin which allows release of virus from infected cells

Question 64

True or False: current HIV drugs are most effective against viruses that are harbored within quiescent T-cells.

Answer 64

False - current HIV drugs require actively replicating virus to be effective; for this reason and the fact that the infection can be latent, it is unlikely that drug treatment will ever eradicate all HIV-infected cells

Question 65

In the context of HIV chemotherapy, it can be said that increases in viral RNA levels despite continued adherence to the drug regimen is indicative of ____ ____.

Answer 65

viral resistance

Question 66

In the context of HIV chemotherapy, treatment failure necessitates changing how many of the drugs in the regimen?

Answer 66

all of them

Question 67

What are the preferred agents for use against HBV polymerase?

Answer 67

Tenofovir disoproxil fumarate and Entecavir

Question 68

What are the preferred agents for treatment of HCV Genotype 1?

Answer 68

Peginterferon-alfa + Ribavirin + Telaprevir, OR Bocepravir HCV NS3/4A protease inhibitors

Question 69

What are the preferred agents for treatment of HCV Genotypes 2&3?

Answer 69

Peginterferon-alfa + Ribavirin

Question 70

How is it that virtually all strains of the influenza A H1N1 virus were resistant to the neuraminidase inhibitor oseltamivir?

Answer 70

overuse of the drugs, including in veterinary applications

Question 71

Is antiviral therapy viracidal or virastatic?

Answer 71

Virastatic - because no therapies will eradicate the virus from the body

Question 72

Based on the steps of the viral life cycle in which they act, order these drugs appropriately: - Atazanavir - Efavirenz - Enfurvitide - Raltegravir

Answer 72

1. Enfurvitide - binding 2. Efavirenz - reverse transcription 3. Raltegravir - integration 4. Atazanavir - proteolysis (translation)

Question 73

What's unusual about Maraviroc compared with other drugs against HIV?

Answer 73

it relies on the fact that the cells infected express the CCR5 receptor; therefore you must know that the cells in question have this target (as opposed to another target like CXCR4)

Question 74

In what 2 ways can resistance to NRTIs occur?

Answer 74

1. alteration of the target | 2. increased repair processes

Question 75

What is the difference in the acyclovir/ganciclovir group of drugs and the abacavir/lamivudine type group of drugs?

Answer 75

the enzymes needed to activate these drugs by phosphorylation: - acyclovir/ganciclovir group uses viral kinase - abacavir/lamivudine group uses host kinases

Question 76

Foscarnet inhibits ____ ____ which prevents viral DNA replication.

Answer 76

pyrophosphate cleavage

Question 77

True or False: drugs that target machinery to prevent viral DNA replication have the chance to inhibit host DNA synthesis, particularly in the mitochondria; thought to be the basis of most drug toxicities.

Answer 77

True

Question 78

How does resistance to NNRTIs occur?

Answer 78

altered target - mutation in the hydrophobic pocket; remember this site is not the enzyme's active site, just the drug's binding site

Question 79

Why is it important for viral genetic material to become incorporated to host DNA?

Answer 79

to hijack and take advantage of the host cell's machinery for replicating

Question 80

What are primary vs. secondary mutations to protease inhibitors (PIs)?

Answer 80

``` primary = first mutations that have only a small effect on resistance secondary = additional mutations that emerge and together with primary mutations confer high level PI resistance ```

Question 81

What is the main reason for using multiple drugs in combination in the treatment of HIV infection?

Answer 81

mainly due to the rapid emergence of resistance; this involves testing the patient's specific infectious strain and selecting a specific treatment regimen

Question 82

Would complete adherence to multidrug HIV treatment likely lead to complete eradication of an infection?

Answer 82

No - because there can be virus living in quiescent T cells

Question 83

What are reasons for treatment failure to HIV drug regimens?

Answer 83

- treatment adherence - development of resistance - subsequent co-infection with new strain

Question 84

Do any of the HIV drugs produce drug-drug interactions through effects upon metabolism?

Answer 84

Yes: - Enfurvirtide is a peptide catabolized to amino acids - Maraviroc uses CYP3A and P-gp - NNRTIs are all CYP substrates; all but one are inducers - PIs are all substrates and inhibitors of CYP3A