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MIC3041 Medical Microbiology > Antivirals > Flashcards

Antivirals Flashcards

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Biology 101 flashcards USMLE® Step 1 flashcards
1
Q

Which blood-borne viruses have no vaccine?

A
  • human immunodeficiency virus (HIV)

- hepatitis C virus (HCV)

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2
Q

What viruses have no vaccine that are not blood-borne?

A
  • Herpesviruses (Herpes simplex virus type-1, HSV-2, Epstein-Barr virus, cytomegalovirus)
  • Enteroviruses (echoviruses, coxsackieviruses)
  • Rhinoviruses (common cold)
  • Paramyxoviruses (resp syncitial virus - RSV)
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3
Q

Why are viral infections hard to treat?

A

They rely on host cell machinery for their own replication

Thus, therapy should target some viral process and not interfere with cellular function (selectivity)

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4
Q

Ideally, an antiviral should NOT be:

A
  • Toxic
  • Mutagenic
  • Teratogenic
  • Carcinogenic
  • Allergenic
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5
Q

What are the 5 viral targets?

A
  1. Attachment and entry to host cell
  2. Uncoating
  3. Genome replication
  4. Expression and processing of viral genes and proteins
  5. Virus assembly
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6
Q

Can different viruses use the same host cell receptor?

A

Yes

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7
Q

How do viruses enter host cells?

A

Viruses have multiple receptor binding sites on their surface, also called virus attachment proteins (VAPs). These interact with host cell receptors. Sometimes they also interact with a host cell co-receptor.

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8
Q

What are host cell receptors?

A

They are cellular proteins which can interact with specific viral proteins.

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9
Q

What type of viral attachment protein do enveloped viruses have?

A

Glycoprotein

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10
Q

What type of viral attachment protein do on-enveloped viruses have?

A

A spike or capsid protein

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11
Q

What are the two processes by which viruses can enter host cells?

A
  1. Endocytosis

2. Fusion

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12
Q

What is the process of fusion? E.g. HIV

A 
Glycoprotein 120 binds to CD4
Conformational change
CCR5 is recruited
Glycoprotein 41 binds to the cell surface
Viral membrane fuses to cell membrane
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13
Q

What is the process of endocytosis?

A

Virus binds to receptor
Coated pit forms
Virus is taken up in an endosome
Virus uncoats and DNA/RNA enters the nucleus

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14
Q

What are some agents that can be used to prevent attachment and entry?

A
  1. Agents which mimic the virus attachment protein
  2. Agents which mimic the host cell receptor
  3. Agents which inhibit fusion
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15
Q

How do agents which mimic the virus attachment protein work?

A

They act by blocking the host cell receptor, however, by doing this it can interfere with cellular functions and may be toxic

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16
Q

How do agents that mimic the host cell receptor work?

A

These are typically antibodies or proteins.
In the case of HIV they can recombinant soluble CD4 receptor peptides. However, whilst they worked well in cell culture they underperformed in clinical trials. High doses were required, which cost more and they weren’t very stable.

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17
Q

How do agents that inhibit fusion work?

A

They target conformation changes that are critical to membrane fusion.
In the case of HIV T20 (Enfuvertide) was developed which inhibited HIV fusion by binding to gp41, preventing the hinging effect and the virus cannot get close enough to the membrane to fuse.

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18
Q

What is T20 (Enfuvertide)?

A

It is an agent that inhibits the fusion of HIV to the cell membrane by binding to gp41, preventing the hinging effect and preventing the virus from getting close to the membrane to fuse.

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19
Q

What are the steps involved in uncoating?

A
  • Release of the viral nucleic acid
  • by change in pH
  • by proteolytic digestion
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20
Q

What are the 3 drugs that inhibit uncoating?

A
  1. Pleconaril (picovir)
  2. Amantidine
  3. Rimantidine
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21
Q

What is Pleconaril (picovir)?

A

It is a broad spectrum anti-viral against picornaviruses, which include enteroviruses and rhinoviruses.
It acts by preventing uncoating.

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22
Q

What is the mode of action of pleconaril (picovir)?

A
  • Binds to a cavity or pocket on the virus capsid
  • Increases the stability of the capsid
  • Protects the capsid from proteolytic digestion
  • Prevents uncoating
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23
Q

Is pleconaril (picovir) approved for use by the FDA?

A

The FDA declined licensing in 2003 as it only had a modest reduction in duration and severity of symptoms.

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24
Q

What is amantidine and rimantidine?

A

They are agents that are active against influenza A, and target the viral matrix protein 2 (M2)

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25
Q

What is the mode of action of amantidine and rimantidine?

A
  • Blocks membrane ion channel formed by M2
  • Prevents pH from dropping
  • Virus cannot uncoat
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26
Q

Is amantidine and rimantidine approved for use by the FDA?

A

Yes, it was approved by the FDA in 1968 and 1994 respectively.

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27
Q

Is resistance an issue for amantidine and rimantidine?

A

Yes, it is an area of great concern

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28
Q

What is a nucleoside?

A

It is a base + sugar (ribose or deoxyribose)

e.g. gaunosine

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29
Q

What is a nucleotide?

A

It is a base + sugar + phosphate

e.g. dGMP, dGDP, dGTP

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30
Q

What are inhibitors of viral replication?

A

Most inhibitors of viral replication are either nucleoside or nucleotide analogues (NAs)

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31
Q

How do most nucleoside/nucleotide analogues (NAs) work?

A

They work by DNA/RNA chain termination

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32
Q

How are NAs classified?

A

They are RNA/DNA polymerase inhibitors

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33
Q

What are the most common antiviral agents?

A

Nucleoside/nucleotide analogues (NAs)

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34
Q

What is an example of a NA and how does it work?

A

An example is Di-deoxy cytosine (ddC), it is the same as the deoxy cytosine that would typically be in the backbone of DNA however it is missing the hydroxyl group on the 5 prime.
Without the hydroxyl group a phosphodiester bond cannot be formed between it and the next nucleotide and the chain is instead terminated.

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35
Q

What is a NA against herpesviruses?

A

Acyclovir - acyclic guanosine analogue

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36
Q

What is acyclovir?

A

It is a NA against HSV-1, HSV-2

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37
Q

Is acyclovir approved for use by the FDA?

A

Yes, it was approved in 1982

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38
Q

What is the mode of action of acyclovir?

A

It is incorporated into the growing DNA strand by thymidine kinase and terminates viral DNA replication

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39
Q

What type of inhibitor is acyclovir?

A

It is a DNA polymerase inhibitor

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40
Q

What are 2 compounds that are related to acyclovir?

A

Ganciclovir and Famciclovir

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41
Q

What is ganciclovir active against?

A

Cytomegaloviruses

42
Q

What is famciclovir active against?

A

Herpes and varicella zoster virus

43
Q

What are the key targets for viral replication in HIV?

A
  • Reverse transcriptase

- Novel viral enzyme

44
Q

What is a NA against reverse transcriptase in HIV?

A

AZT, which is a thymidine analogue

45
Q

What is AZT?

A

It is a NA, thymidine analogue, against reverse transcriptase in HIV

46
Q

Is AZT approved for use by the FDA?

A

Yes, it was first licensed in 1987

47
Q

What is the mode of action of AZT?

A

It is phosphorylated by host cell kinases and causes DNA termination

48
Q

Does AZT have side effects?

A

Yes

49
Q

What are more efficacious NA compared to AZT?

A

Lamivudine and Tenofovir

50
Q

What is Truvada?

A

It is a NA against HIV consisting of tenofovir and emtricitabine

51
Q

What is pre-exposure prophylaxis (PrEP) for HIV?

A

It is an anti-viral, Truvada, to be used for HIV-negative people at higher risk of developing HIV to prevent infection

52
Q

What is tenofovir?

A

It is a nucleotide analogue of adenosine monophosphate

53
Q

What is emtricitabine?

A

It is a nucleoside analogue of cytodine

54
Q

Is Truvada available in Australia?

A

Yes, it was added to the PBS in 2018

55
Q

What schedules is PrEp/Truvada available in?

A

It is available in two schedules: daily dosing and on-demand

56
Q

How much does PrEp/Truvada reduce the risk of acquisition of HIV?

A

99%

57
Q

How does Hepatitis B replicate?

A

It has a DNA genome with an RNA intermediate, requiring RNA transcriptase

58
Q

Which drugs developed for HIV also work on Hepatitis B?

A

Lamivudine

Tenofovir

59
Q

What are some licensed NA for Hepatitis B?

A

Lamivudine
Adefovir
Entecavir
Tenofovir

60
Q

Is resistance an issue with NA for Hepatitis B?

A

Yes with long-term use

61
Q

What are the first line agents for Hepatitis B infection?

A

Entecavir and Tenofovir, as they have low resistance rates

62
Q

Other than NAs, what are another type of agent that prevent viral replication?

A

Non-nucleotide RT inhibitors (NNRTIs)

63
Q

What are 2 examples of NNRTIs for HIV?

A

Efavirenz and Rilpivirine

They are second generation

64
Q

What is the mode of action of efavirenz and rilpivirine?

A

They bind to a unique binding site on one of the subunits of HIV reverse transcriptase (p66), causing a conformational change

65
Q

What are efavirenz and rilpivirine?

A

They are second generation NNRTIs against HIV

66
Q

Are efavirenz and rilpivirine substrates for p66?

A

No, but they can inhibit it by changing the conformation of the enzyme

67
Q

Where do efavirenz and rilpivirine bind to on p66?

A

They bind to either dNTP binding site or the RT catalytic site

68
Q

Is resistance an issue with efavrienz and rilpivirine?

A

Yes

69
Q

What type of fidelity do reverse transcriptase and RNA polymerase have?

A

Poor fidelity

70
Q

What are quasispecies?

A

They are new species of viruses that emerge through mutations occurring in viral replication

71
Q

What is incomplete suppression?

A

It is when after reducing the amount of virus through anti-virals an increase is seen with the increase being mostly comprised of drug-resistant variants

72
Q

What are 3 things that can cause incomplete suppression?

A
  • Inadequate potency/drug levels
  • Inadequate adherence
  • Pre-existing resistant variants
73
Q

How do resistant variants rise?

A

Selection of a minor quasispecies

Amplifaction by selection pressure

74
Q

How does HIV develop resistance?

A

With long-term treatment

  • Reverse transcriptase has no “proof-reading” capacity
  • Misincorporation of nucleotides leads to swarms of closely related viral genomes - quasispecies
  • By natural selection, the fittest becomes dominant
75
Q

How do we overcome HIV resistance?

A

It can be overcome by combination anti-viral therapy

76
Q

What is HAART?

A

Highly Active AntiRetroviral Therapy
Now called ART
Combination antiviral therapy

77
Q

What amino acid changes are present in Lamivudine resistance?

A

L180M

M204V

78
Q

What are proteases?

A

They are enzymes that cleave viral polypeptides

79
Q

What was the first protease to have its 3D crystal structure determined?

A

HIV protease

80
Q

What are 3 examples of HIV protease inhibitors?

A

Indinavir
Darunavir
Saquinavir

81
Q

What is the mode of action of protease inhibitors?

A

Protease inhibitors are designed to fill binding pockets of the protease (7 aa peptides which mimic the substrate protein)

82
Q

Are Hepatitis C protease and polymerase inhibitor approved for use?

A

Yes

83
Q

What is interferon?

A

It is known as the “magic bullet” due to having multiple modes of antiviral action
- It is part of the innate immune system in humans

84
Q

What is the mode of action of interferon?

A

It induces the synthesis of antiviral molecules but non-specific
Results in inhibition of viral mRNA production and translation
Can also inhibit virus assembly

85
Q

What was interferon used for?

A

Was used to treat Hepatitis B and C
However, clinical effects were disappointing
It was a long term treatment - 6-12 months
It also had adverse side effects

86
Q

What are DDAs?

A

They are Direct Acting Antivirals developed for Hepatitis C in 2016

87
Q

What are the targets for DDAs?

A
  • Protease inhibitors
  • NS5A inhibitors
  • Polymerase inhibitors (Sofosbuvir)
88
Q

What is NS3/4A inhibitor?

A

It acts against Hepatitis C
It targets NS3/4A which is a protease responsible for cleaving NS4B, NS5A and NS5B
It binds to NS3/4A preventing it from cleaving

89
Q

How many people in Australia are living with chronic Hepatitis C infection?

A

230,000

90
Q

How many new cases of Hepatitis C in Australia each year?

A

10,000

91
Q

How many people sough treatment and what was the outcome?

A

Only 2000-3000 people sought treatment and received peglycated interferon + ribavirin which has low cure rate of 50% and has serious adverse effects (SAE)

92
Q

When did DDAs for Hepatitis C go on the PBS?

A

2016 with a greater than 95% cure rate and few SAEs

93
Q

What is the significance of Hepatitis C infection?

A

399,000 deaths globally each year
583 deaths in Australia in 2017
66 liver transplants in Australia in 2017

94
Q

What does neuraminidase do?

A

Viral neuraminidase is present in influenza A and B, it acts by cleaving the terminal sialic acid of cells (the viral receptor) and allows the virus to spread

95
Q

What is the mode of action of neuraminidase inhibitors?

A

They are sialic acid analogues that competitively inhibit the viral neuraminidase, this prevents the release of virus budding from the cell

96
Q

What are 2 examples of neuraminidase inhibitors?

A

Relenza (Zanamivir)

Tamiflu (Oseltamivir)

97
Q

What is Relenza (Zanamivir)?

A

It is a neuraminidase inhibitor that is taken as an inhalant (powder form)

98
Q

What is Tamiflu (Oseltamivir)?

A

It is a neuraminidase inhibitor that is orally bioavailable, and comes in a tablet

99
Q

When should Relenza (Zanamivir) and Tamiflu (Oseltamivir) be used?

A

They should be used within 2 days of illness

100
Q

What do Relenza (Zanamivir) and Tamiflu (Oseltamivir) do?

A

They reduce the duration and symptoms of disease

They are also licensed for prophylactic use

101
Q

What is the next generation of neuraminidase inhibitor being investigated?

A

Laninamivir

MIC3041 Medical Microbiology (11 decks)

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