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MM- Viruses > Antivirals > Flashcards

Antivirals Flashcards

1
Q

What is required by a good antiviral?

A
  • High therapeutic index
  • Easy to administer
  • Easy to store
  • Cheap to produce
  • Broad scale use
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2
Q

What is a high therapeutic index?

A

This is an antiviral which has a high antiviral activity but low cellular toxicity

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3
Q

What is helping us to develop new anti-viral drugs?

A

Rational drug design
3D structures of molecules
Crystal structures

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4
Q

What are the nucleoside analogue chain terminators you must know?

A
  • HSV: Ganciclovir and acyclovir
  • HCV: Ribavarin
  • HIV: AZT: Azidothymidine
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5
Q

What nucleoside analogues can be used to treat HSV infection?

A

Acyclovir and ganciclovir

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6
Q

Acyclovir is a?

A

Prodrug

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7
Q

Acyclovir action?

A

It is phosphorylated by the viral thymidine kinase to become acyclovirir-monophosphate
It is then phosphorylated into acycloviur-triphosphate by cellular kinases and can act as a chain terminator during DNA synthesis

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8
Q

How does acyclovir prevent cellular toxicity?

A

It has a higher affinity for viral polymerase than for host polymerase

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9
Q

What is the main difference between ganciclovir and acylclovir?

A

Ganciclovir has an additional hydroxymethyl group

Ganciclovir must be injected and cannot be applied topically like acyclovir

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10
Q

Why is acyclovir easier to administer?

A

Topical application is possible

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11
Q

What is the nucleoside analogue used to treat HCV hepatitis C infection?

A

Ribavirin which is a chain terminator

It is a guanosine analogue

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12
Q

What nucleoside analogue can be used for HIV treatment?

A

Azidothymidine = AZT

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13
Q

Azidothymidine is what class of drug?

A

NRTI

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14
Q

What is an NRTI?

A

Nucleoside reverse transcriptase inhibitor

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15
Q

How can resistance to AZT develop?

A

Via mutations in the gene encoding the reverse transcriptase

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16
Q

What therapy is used in HIV treatment?

A

HAART

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17
Q

What does HAART stand for?

A

Highly active anti retroviral therapy

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18
Q

What does HAART therapy involve?

A

It involves the use of multiple antivirals which when used in combination should reduce resistance developing

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19
Q

What is used in combination therapy for HIV?

A 
Integrase inhibitors
Protease inhibitors
NRTI nucleoside RT inhibitors
NNRTI non-nucleoside RT inhibitors
Entry inhibitors
Anti-fusion class of drugs
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20
Q

What is an example of a HIV entry inhibitor?

A

Maraviroc

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21
Q

What does Maraviroc do?

A

It binds to CCR5 and prevents HIV binding

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22
Q

What homozygous mutation makes individuals resistant to HIV?

A

CCR5-delta 32

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23
Q

The first man cured of HIV?

A

Timothy Brown- 2007

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24
Q

How was Timothy Brown cured of HIV?

A

He has leukaemia and was given a haematopoietic stem cell transplant from a donor who was homozygous for the CCR5 delta 32 mutation

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25
Q

Why are so many drugs against HIV required?

A

So they can be used in combination to reduce the likelihood that resistance will develop

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26
Q

What is the name of the HIV combination therapy?

A

HAART

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27
Q

HAART stands for?

A

Highly active anti retroviral therapy

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28
Q

The CCR5 delta 32 mutation is most common in?

A

Caucasians

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29
Q

Drugs against rhinovirus include?

A

Pocket factor lipid mimics

IMP-1088

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30
Q

Which drugs target the host?

A

Maraviroc targeting host CCR5

Imp-1088 targeting the host N-myrostoyltransferase

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31
Q

Which drug can mimic the pocket factor lipid?

A

Pleconaril

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32
Q

What is the host N-myristoyltransferase used for?

A

To N’ myristoylate the VP0. This allows assembly of the capsid

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33
Q

What drugs can be used against HCV?

A
  • Ribaravin nucleoside chain terminator
  • Drugs targeting NS5B polymerase
  • Anti-protease drugs targeting NS3/4A
  • NS5A inhibitors
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34
Q

NS5A is involved in?

A

Formation of the membranous web

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35
Q

Ribaravin is what?

A

A nucleoside chain terminator, guanosine analogue

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36
Q

What drugs can target the NS5B polymerase?

A

Sofosbuvir

37
Q

What drugs can target the NS3/4A?

A

Telaprevir

38
Q

Sofosbuvir targets?

A

The NS5B polymerase of HCV

39
Q

Telaprevir targets?

A

the NS3/4A protease of HCV

40
Q

Which drug targets the M2 ion channel of influenza?

A

Amantadine

41
Q

Which drugs target the neuraminidase?

A

Tamiflu and Relenza

42
Q

Tamiflu can also be known as?

A

Oseltamivir

43
Q

Relenza can also be known as?

44
Q

Resistance against amantadine has been seen in?

A

In H5N1, due to overuse in poultry industry

In the pH1N1 of 2009, probably do to overuse in pig farming

45
Q

Tamiflu/oseltamivir action?

A

It has a hydrophobic group which binds to the hydrophobic pocket

46
Q

Relenza/zanamivir action?

A

Sialic-guanadine analogue

Blocks neuraminidase

47
Q

What helped to create these two drugs?

A

Crystalline structure of neuraminidase allowed for rational drug design

48
Q

Tamiflu was developed by?

49
Q

Relenza was developed by?

50
Q

Why is tamiflu used more frequently than relenza?

A

Relenza has to be inhaled using an inhalation device which the elderly often find difficult to use, it is also more difficult to store

51
Q

Why is tamiflu better than amantadine?

A

Effective against influenza A and B

52
Q

Amantadine is not effective against?

A

Influenza B

53
Q

Which anti-influenza drug does the government tend to stockpile and why?

A

Tamiflu as it is in a pill form which makes it easy to store
The government will require something to give people in the event of a pandemic as vaccines usually take around 6 months to develop

54
Q

Cochrane researchers did what?

A

They investigated the efficacy of Tamiflu and Relenza and wanted to evaluate whether stockpiling the drugs was worthwhile

55
Q

Cochrane results?

A

4% associated nausea and vomiting
Reduces infection by 17 hours in adults and 29 hours in children
Revisiting the 2009 pandemic these drugs reduced death associated with infection by 50% when administered within 48 hours of developing symptoms

56
Q

Tamiflu resistance has been observed in?

57
Q

Spontaneous tamiflu resistance was observed where?

A

H1N1

Norway

58
Q

How did spontaneous tamiflu resistance develop?

A

Due to natural drift in gene encoding neuraminidase in response to the selection pressure imposed by the immune system

59
Q

What replaced seasonal H1N1?

A

Pandemic H1N1 from the 2009 pandmeic

60
Q

What mutation caused spontaneous tamiflu resistance in seasonal H1N1?

A

H274Y mutation

61
Q

Which antivirals can target the polymerase of influenza?

A

Baloxavir

Favipiravir

62
Q

Baloxavir targets?

A

PA endonuclease

63
Q

Favipiravir targets?

A

PB1 polymerase

64
Q

What mutation caused the spontaneous tamiflu resistance of seasonal H1N1?

65
Q

H274Y is from?

A

Histidine to tyrosine

66
Q

E627K mutation is?

A

From glutamate to lysine

Allowing the shorter ANP32A to be used

67
Q

H274Y mutation is from?

A

Histidine to tyrosine

68
Q

H274Y mutation conferred resistance to?

69
Q

What are monoclonal antibodies?

A

Identical antibodies are antibodies produce by identical immune cells which are clones of a unique parent cell

70
Q

What are monoclonal antibodies?

A

Identical antibodies which are produced by identical cells which are clones of a unique parent cell

71
Q

What is passive immunotherapy?

A

Giving antibodies from an individual that was infected and survived to another individual

72
Q

What was the first method of producing monoclonal antibodies?

A

Murine hybridoma

73
Q

Hybridoma?

A

Fusing an antibody producing B cell line with a myeloma cell line

74
Q

What was the issue with this method?

A

The humans injected with murine antibodies would produce antibodies against these as they were recognised as foreign

75
Q

How was this circumenvented?

A

Chimeric antibodies and humanised antibodies

76
Q

What are chimeric antibodies?

A

These are antibodies in which the the murine antibody constant regions have been replaced by human antibody constant regions

77
Q

What are humanised antibodies?

A

These are antibodies in which only the CDR- complementary determining regions which bind the epitopes are of murine origin

78
Q

What is an example of a humanised antibody?

A

Palivizumab

79
Q

Palivizumab is given to?

A

Premature babies, children with special conditions to protect them against RSV infection

80
Q

Palivizumab is given to children to protect them from developing?

A

Bronchiolitis

81
Q

What does Palivizumab target?

A

F protein of RSV

82
Q

Humanised antibodies used in the Ebola outbreak?

A

Cocktail of 3 humanised monoclonal antibodies targeting 3 epitopes of the Ebola glycoprotein

83
Q

How was this humanised monoclonal antibody cocktail made?

A

It was produced in GM tobacco plants

84
Q

What was this Ebola therapy known as?

A

Zmapp therapy

85
Q

How can fully humanised antibodies be made?

A

GM mice

Or direct immortalisation of human B cells

86
Q

Using GM mice?

A

Using GM mice which contain human genes encoding antibodies rather than mice genes… then fusion to a myeloma cell line

87
Q

Direct immortalisation of human B cells?

A

Fusing B cell producing the desired antibodies with e.g. EBV

88
Q

What is the modern method of monoclonal antibody production?

A

Phage display

89
Q

Who came up with phage display?

A

Greg Winter

MM- Viruses (13 decks)

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