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Mechanism of antivirals Flashcards

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USMLE® Step 1 flashcards Biology 101 flashcards
1
Q

What are the uses of anti-virals?

A
  • Treatment of acute infection
  • Treatment of chronic infection
  • Post-exposure prophylaxis(PEP) and preventing infection
  • Pre-exposure prophylaxis(PrEP)
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2
Q

What is selective toxicity?

A

When a drug has a selective action against one component and not another

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3
Q

What is selective toxicity due to?

A

Due to the differences in structure and metabolic pathways between host and pathogen

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4
Q

What do antiviral harm?

A

Harm microorganisms, not the host

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5
Q

What should the target of the antiviral be?

A

We need for the target of the antiviral to be in the microbe, not in the host

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6
Q

Why is it difficult to make antivirals for viruses?

A

Difficult to make antivirals for viruses because viruses are intracellular organisms and use cellular machinery to replicate themselves,

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7
Q

Why is it difficult to make anti-fungal and anti-parasitic drugs?

A

Difficult to make antifungal and anti-parasitic drugs as well because they can be very similar to the host so hard to make something that only harms the microbe and not the host

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8
Q

Why is it difficult to develop effective, non-toxic antivirals?

A
  • Viruses enter cells using cellular receptors which may have other functions
  • Viruses must replicate inside cells – obligate intracellular parasites
  • Viruses take over the host cell replicative machinery
  • Viruses have high mutation rate - quasispecies
  • Anti-virals must be selective in their toxicity
    i. e. exert their action only on infected cells
  • Some viruses are able to remain in a latent state e.g. herpes, HPV
  • Some viruses are able to integrate their genetic material into host cells
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9
Q

What is the life cycle of a virus?

A
  1. Virus enters and attaches to membrane
  2. Gets internalized by endocytosis or membrane fusion
  3. Once the virus is inside it has to uncoat and release its genome
  4. Genome replicates and makes mRNA
  5. mRNA goes to the ribosomes where it starts makes viral proteins
  6. Virus reassembles
  7. Virus can escape through cell lysis or budding and release
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10
Q

What do antiviral prevent?

A
  • Preventing virus adsorption onto host cell
  • Preventing penetration
  • Preventing viral nucleic acid replication
  • Preventing maturation of virus
  • Preventing virus release
  • Prevents uncoating
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11
Q

What do acyclovir, ganciclovir and ribavirin target?

A

Target reverse transcriptase’s or DNA polymerases

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12
Q

What is ribavirin and what does it compromise?

A

Ribavirin is a GTP analogue so compromises genome replication as it can’t make it’s genome because there are not enough precursors of like deoxy GTP

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13
Q

How does amantadine work and what does it prevent?

A

When virus enters the cell, it fuses its membrane with the liposome membrane from amantadine to prevent uncoating of the virus

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14
Q

What are examples of selective toxicity viral targets?

A
  • Thymidine kinase
  • Proteases from the genome of HIV
  • Reverse transcriptase of HIV
  • DNA polymerases
  • Neuraminidase of influenza virus
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15
Q

What does herpes virus include?

A
  • Herpes simplex (HSV),
  • Varicella Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Epstein-Barr virus (EBV)
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16
Q

What treatments are available for herpes?

A
  • Acyclovir
  • Ganciclovir
  • Forcarnet
  • Cidofovir
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17
Q

How is acyclovir administred?

A

IV/oral/topical

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18
Q

What is acyclovir for?

A

For HSV,VZV treatment/prophylaxis

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19
Q

What is acyclovir good at?

A

Good at CMV/EBV prophylaxis but not as a treatment

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20
Q

How is ganciclovir administred?

A

IV/Oral

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21
Q

What is ganciclovir for?

A

For CMV

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22
Q

How is forcarnet administred?

A

IV/local application

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23
Q

What is forcarnet for?

A

For CMV

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24
Q

How is cidofovir administred?

A

IV

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25
Q

What is cidofovir for?

A

For CMV

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26
Q

What is Acyclovir?

A

Acyclovir is a GTP analogue

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27
Q

What has acyclovir lost and why? What is this known as?

A

Has lost part of its ribose sugar

  • Normally need 3’ hydroxyl group on the sugar molecule to add a nucleotide but this does not have it so nucleotides can no longer be added
  • Is known as a chain terminator
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28
Q

Why does acyclovir need to be activated?

A

Is a prodrug so needs to be activated

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29
Q

Steps involved in the activation of acyclovir

A
  • Phosphorylated first by a viral thymidine kinase
  • One phosphorylated, it remains stable within the cell
  • Then gets di and triphosphorylated by cellular kinases
  • Only in the triphosphorylated form it becomes active
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30
Q

What is thymidine kinase?

A

Thymidine kinase is an enzyme encoded by the genome of the virus

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31
Q

What does acyclovir become once its activated?

A

Then becomes a competitive inhibitor for the natural substrate for DNA polymerase

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32
Q

What does acyclovir compete for and hence what does this stop?

A

Competes for GTP so stops the viral polymerase from synthesizing viral genome

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33
Q

Where is acyclovir selectively activated in?

A

Is selectively activated only in cells that are infected

-Because it is phosphorylated by viral thymidine kinase

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34
Q

Thymidine kinase compared to acyclovir affinity

A

HSV thymidine kinase (TK) has 100x the affinity for ACV compared with cellular phosphokinases

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35
Q

Activated acyclovir compared to HSV DNA polymerase affinity

A

Acyclovir triphosphate has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase

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36
Q

Polarity of Acyclovir compared to activated acyclovir and discuss the comparison

A

Acyclovir triphosphate is a highly polar compound - difficult to leave or enter cells
- But acyclovir is easily taken into cells prior to phosphorylation

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37
Q

What is ganciclovir active for?

A

Active for CMV

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38
Q

What does a congenital infection with CMV cause?

A

Congenital infection with CMV causes congenital infections in newborn

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39
Q

What is the structure of ganciclovir similar to?

A

Structurally similar to acyclovir

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40
Q

What kinase does CMV encode and not encode?

A

CMV does not encode TK but has UL97 kinase

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41
Q

Why can CMV not activate acyclovir?

A

Cannot activate acyclovir effectively as no phosphorylation by TK

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42
Q

What does UL97 kinase activate better?

A

UL97 kinase activates ganciclovir better than it can activate ACV so ganciclovir works better for CMV

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43
Q

What state is ganciclovir inside the cell and what does it compete for?

A

Similar to ACV, ganciclovir is di and triphosphorylated inside the cell via cellular kinases
-Then competes for the natural substrate for DNA polymerase and blocks the ability of the virus to make its own DNA

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44
Q

What does ganciclovir inhibit?

A

Inhibits CMV DNA polymerase

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45
Q

What is foscarnet used for?

A

Used for CMV infection in the immunocompromised

46
Q

What does foscarnet selectively inhibit and how?

A

Selectively inhibits viral DNA/RNA polymerases

  • Binds pyrophosphate binding site in the DNA polymerases– a structural mimic
  • DNA polymerase can therefore not make DNA
47
Q

Does foscarnet require activation?

A

No activation required as its not a prodrug

48
Q

Why is foscarnet used in cases of TK mutants in CMV?

A

Used in cases of TK mutants because it targets a different site to ganciclovir

49
Q

What is cidofovir and what does it target?

A

Chain terminator - targets DNA polymerase

50
Q

What does cidofovir compete with?

A

Competes with dCTP

51
Q

What type of analogue is cidofovir?

A

Monophosphate nucleotide analogue

52
Q

What is cidofovir active against when you cant use ganciclovir?

A

drug active against CMV when you can’t use ganciclovir but MUCH MORE nephrotoxic

53
Q

What is cidofovir for the treatment of?

A

Treatment of retinitis in HIV

54
Q

What are the 2 mechanisms for the resisitance to anti-virals in herpes viruses?

A
  1. Thymidine kinase mutants

2. DNA polymerase mutants

55
Q

What happens if TK mutates?

A

If TK mutates: can no longer activate prodrug

56
Q

What happens if DNA polymerase mutates?

A

If DNA polymerase mutates i.e. the active site: the activated drug can no longer bind

57
Q

Structural features of HIV

A

Check notes

58
Q

What is the life cycle of HIV?

A
  1. Attachment with binding of viral gp102 via CD4 and CCRX
  2. Reverse transcription of RNA into dsDNA
  3. Integration into host chromosome of proviral DNA
  4. Transcription of viral genes
  5. Translation of viral Mrna into viral proteins
  6. Virus assembly and release by budding
  7. Maturation
59
Q

Examples of anti-HIV drugs

A
  1. Anti-reverse transcriptase inhibitors
  2. Protease inhibitors – multiple types
  3. Integrase inhibitors
  4. Fusion inhibitors – gp120/41 – biomimetic lipopeptide
  5. Treatment – HAART (Highly Active Anti Retro Viral Therapy)
60
Q

What do nukes(nucleoside RT inhibitors do)?

A

▪ Block RT enzyme by mimicking nucleosides/nucleotides

61
Q

What effect do non-nukes have?

A

have an allosteric effect

62
Q

What happens if you block proteases in viral genome?

A

○ If you block the proteases in the viral genome, the virus cannot assemble itself

63
Q

What gene is involved in integrase inhibitors?

A

○ POL gene

64
Q

What does the POL gene encode for?

A

The POL gene encodes for three separate components: protease, reverse transcriptase and integrase (IN) with the 3´end encoding for IN (polynucleotidyl transferase)

65
Q

What does integrase allow?

A

▪ Integrase allows crosslinking of viral DNA into host DNA

66
Q

What do integrase inhibitors target?

A

○ Integrase inhibitors target integrase enzyme so virus is not permanently established into host germline

67
Q

What do viruses use to fuse with cell membrane?

A

Virus fuses with the cell membrane using gp120 glycoprotein on surface and gp41

68
Q

What do fusion inhibitors interrupt?

A

○ Fusion inhibitors interrupt gp120/41 interaction

69
Q

What is HAART(Highly active antiretroviral therapy)

A

○ Combination of drugs used to avoid resistance

70
Q

What is zidovudine an example of?

A

An example of nucleoside reverse transcripatse

71
Q

What is zidovudine an analogue of?

A

○ Synthetic analogue of nucleoside thymidine

72
Q

What does zidovudine have at the end of its chain instead of a 3’ hydroxyl group and what does it act as?

A

○ Normally thymide has a 3’ hydroxyl group but this has an azide group
§ Acts as a chain terminator

73
Q

What is zidovudine converted into to block reverse transcriptase and how does it do so?

A

When converted to tri-nucleotide by cell enzymes, it blocks RT by - competing for natural nucleotide substrate dTTP

74
Q

what is nevirapine an example of?

A

NON NUCLEOSIDE REVERSE TRANSCRIPTASE (RT) INHIBITORS

75
Q

Why does nevirapine have a completely different effect and what deos it do?

A

Has a completely different effect as bind to enzyme in completely different way but still inhibits it

76
Q

What is nevirapine a non-competitive inhibitor of?

A

○ Non-competitive inhibitor of HIV-1 RT

77
Q

What is nevirapine a strong synergistic with and why?

A

Strong synergistic with NRTI’s such as AZT because of different mechanisms – combination works well

78
Q

When is PEP taken?

A

○ within 72 hours post exposure

▪ Must take it quickly because once it gets inside the bloodstream, HIV spreads very quickly

79
Q

What does PEP usually consist of?

A

○ Usually consists of 2x NRTIs + integrase inhibitor

80
Q

How long do you have to take PEP?

A

○ Must take for 28 days

81
Q

What does PrEP contain?

A

2x NRTIs

82
Q

When is PrEP taken?

A

○ two tablets 2 – 24 hours before sex

○ One 24 hours after sex and a further tablet 48 hours after sex - called ‘on-demand’ or ‘event based’ dosing

83
Q

What does 2 NRTI’s mean?

A

○ Combination of Nucleoside RTIs
○ Emtricitabine (guanosine analog) + tenofovir (adenosine analog)
§ Effective because you are essentially competing twice for two different substrates of the enzyme

84
Q

Why is there mutation to anti-virals?

A

○ Mutation rate of viruses is high
○ High viral load so you are likely to generate a mutant
○ Use of single agents leads to rapid development of resistance
○ The drug binding site is altered in structure by as few as one amino acid substitution

85
Q

What does HIV form within an individual?

A

○ They form a quasispecies within an individual patient: - a viral swarm

86
Q

Why is a combination of antivirals used?

A

Chances of becoming resistant to one drug is high but becoming resistant to more than one drug is much less likely

87
Q

What are drugs used for the influenza virus?

A
  1. Amantadine

2. Zanamivir and oseltamivir

88
Q

What does amantadine inhibit?

A

Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin

89
Q

What is M2 involved in?

A

M2 is involved in acidifying the early endosome when the virus enters the cell

90
Q

What happens if there is no M2?

A

▪ If no M2, it cannot acidify it’s membrane does not fuse with the endosome and so the viral nucleic acid is not released into the cytoplasm

91
Q

When does zanamivir and oseltamivir work?

A

○ Only works if you take it in the first 24 hours of being exposed

92
Q

Why is zanamivir and oseltamivir taken?

A

taken to dampen down an epidemic because it prevents the virus from spreading

93
Q

What does zanamivir and oseltamivir inhibit and via what?

A

Inhibits virus release from infected cells via inhibition of neuraminidase enzyme

94
Q

What does neuraminidase do?

A

Neuraminidase cleaves off sialic acid from the receptor on the cell surface allowing the release of the virus

95
Q

How is oseltamivir taken?

A

Oral

96
Q

How is zanamivir taken?

A

Inhaled or IV

97
Q

What is not used and used, post exposure to hepatitis B?

A

Don’t use antiviral, take passive antibodies to neutralize virus particles that may have entered the body, followed by vaccination

98
Q

When are antivirals only used post exposure to hepatitis B?

A

If someone had active, high E antigen shedding hep B infection, only then are antivirals used

99
Q

What is used to treat hepatitis C, post exposure?

A

Interferon-g + ribavarin (anti-viral) for 6 months

100
Q

What does Interferon-g + ribavarin (anti-viral) for hepatitis C work as and why?

A

• This works as a boost of immunity as there were no drugs that worked well against Hep C

101
Q

Structure of Hepatitis C virus?

A

9.6 Kb RNA virus, enveloped

102
Q

How is hepatitis C transmitted?

A

Transmitted via blood – infectious

103
Q

What is hepatitis C a major cause of?

A

Major cause of chronic liver disease

104
Q

What does Ribavirin do?

A

Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase

105
Q

How does ribavirin work?

A

○ this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)
○ and thereby stops GTP synthesis and consequently, RNA synthesis
○ If there is no RNA, it cannot make new viruses

106
Q

What are DAA’s for HCV acting on?

A

○ Acts to target specific steps in the HCV viral life cycle

107
Q

What do DAA’s block?

A

Block polyprotein processing

108
Q

Why is polyprotein processing essential for virus?

A

If polyproteins are not processed, they cannot make the enzymes that are essential for the cell

109
Q

What do DAA’s inhibit?

A

○ Hep C polymerase inhibitors

○ NS5A inhibitor

110
Q

What does inhibiting NS5A block?

A

○ Block replication, complex assembly and formation by blocking enzymes needed for budding, maturation and release

Medical microbiology (14 decks)

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