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CMOD/PCM- Block 2 > Pharm: Anti-Viral Mechanisms > Flashcards

Pharm: Anti-Viral Mechanisms Flashcards

1
Q

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

A

only one or a few viruses; multiple bacterial species

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2
Q

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

A

Attachment and entry

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3
Q

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

A

the action of the viral M2 ion channel protein; uncoating

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4
Q

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

A

polymerAZE inhibitors; genome replication

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5
Q

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

A

inhibitor of integrase; genome replication

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6
Q

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

A

protease inhibitors; assembly and maturation

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7
Q

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

A

neuraminidase inhibitors; egress and release

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8
Q

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

A

nucleoside; viral DNA polymerase

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9
Q

The HIV virus infects ____ cells.

A

CD4+

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10
Q

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.

A

gp41 and gp120 proteins

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11
Q

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

A

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

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12
Q

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

A

reverse transcriptase

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13
Q

What reaction depends on HIV-encoded integrase?

A

integration of HIV DNA into the host cell genome

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14
Q

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

A

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

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15
Q

Viral HIV mRNA is translated into proteins on what machinery?

A

host cell ribosomes

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16
Q

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

A

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

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17
Q

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.

A

hemagglutinin; sialylated glycoprotein; receptor-mediated endocytosis

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18
Q

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

A

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

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19
Q

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

A

viral RNA-dependent RNA polymerase

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20
Q

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

A

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

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21
Q

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

A

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

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22
Q

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

A

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

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23
Q

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

A

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

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24
Q

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.

A

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

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25
Q

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

A

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

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26
Q

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

A

nucleoside inhibitors and non-nucleoside inhibitors

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27
Q

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

A

metabolic activation; intracellular phosphorylation by kinases

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28
Q

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

A

herpes and HIV

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29
Q

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

A

termination of DNA chain elongation

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30
Q

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

A

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

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31
Q

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

A

Deoxyguanosine triphosphate (dGTP) aka pppdG

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32
Q

What does “NRTI” stand for?

What function do they inhibit and how?

A

“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

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33
Q

What are NNRTIs and how are they different from NRTIs?

A

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

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34
Q

What is a Thymidine analogue mutation?

A

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

35
Q

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

A

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

36
Q

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

A

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

37
Q

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

A

True

38
Q

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

A

diphosphate form; deoxyadenosine triphosphate

*Aid: ADEfovir and ADEnosine

39
Q

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

A

False - Adefovir has a higher affinity for HBV DNA polymerase

40
Q

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

A

triphosphate form; HBV; deoxyguanosine triphosphate

41
Q

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

A

weak inhibitor

42
Q

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

A

triphosphate form; HBV

43
Q

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

A

triphosphate; HBV; thymidine 5”-triphosphate

44
Q

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

A

little toxicity

45
Q

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

A

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

46
Q

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

A

thymidylate synthase; DNA synthesis

47
Q

How likely is viral resistance to Trifluridine?

A

rare

48
Q

Raltegravir blocks catalytic activity of what?

A

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

49
Q

How can a virus become resistant to Raltegravir?

A

primary mutations in the integrase gene

50
Q

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

A

aspartyl protease

51
Q

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

A

metamorphosis of HIV particles into their mature infectious form

52
Q

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

A

HIV-1 protease inhibitors

*Aid: recognize names by common suffix: “vowel-navir”

53
Q

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

A

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

54
Q

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

A

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

55
Q

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

A

interferon; polyethylene glycol

56
Q

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

A

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

57
Q

How do the effects of interferon inhibit viral RNA transcription?

A

activates Mx protein, blocks viral RNA synthesis

*Mx=cellular protein with anti-viral activity, induced by IFN-binding

58
Q

How do the effects of interferon inhibit viral RNA translation?

A

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

59
Q

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

A

inhibits glycosyltransferase, thereby reducing protein glycosylation

60
Q

How do the effects of interferon inhibit virus maturation?

A

inhibits glycosyltransferase, thereby preventing glycoprotein maturation

61
Q

How do the effects of interferon inhibit virus release?

A

causes membrane changes that blocks virus budding

62
Q

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

A

sialic acid; influenza-A and -B neuraminidases

63
Q

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

A

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

64
Q

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

A

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

65
Q

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 ____ ____.

A

viral resistance

66
Q

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

A

all of them

67
Q

What are the preferred agents for use against HBV polymerase?

A

Tenofovir disoproxil fumarate and Entecavir

68
Q

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

A

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

69
Q

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

A

Peginterferon-alfa + Ribavirin

70
Q

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

A

overuse of the drugs, including in veterinary applications

71
Q

Is antiviral therapy viracidal or virastatic?

A

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

72
Q

Based on the steps of the viral life cycle in which they act, order these drugs appropriately:

  • Atazanavir
  • Efavirenz
  • Enfurvitide
  • Raltegravir
A
  1. Enfurvitide - binding
  2. Efavirenz - reverse transcription
  3. Raltegravir - integration
  4. Atazanavir - proteolysis (translation)
73
Q

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

A

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)

74
Q

In what 2 ways can resistance to NRTIs occur?

A
  1. alteration of the target

2. increased repair processes

75
Q

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

A

the enzymes needed to activate these drugs by phosphorylation:

  • acyclovir/ganciclovir group uses viral kinase
  • abacavir/lamivudine group uses host kinases
76
Q

Foscarnet inhibits ____ ____ which prevents viral DNA replication.

A

pyrophosphate cleavage

77
Q

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.

A

True

78
Q

How does resistance to NNRTIs occur?

A

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

79
Q

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

A

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

80
Q

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

A 
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
81
Q

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

A

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

82
Q

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

A

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

83
Q

What are reasons for treatment failure to HIV drug regimens?

A
  • treatment adherence
  • development of resistance
  • subsequent co-infection with new strain
84
Q

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

A

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

CMOD/PCM- Block 2 (41 decks)

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