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MIC3041 Medical Microbiology > Antivirals > Flashcards

Antivirals 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
What is the mode of action of amantidine and rimantidine?
- Blocks membrane ion channel formed by M2 - Prevents pH from dropping - Virus cannot uncoat
26
Is amantidine and rimantidine approved for use by the FDA?
Yes, it was approved by the FDA in 1968 and 1994 respectively.
27
Is resistance an issue for amantidine and rimantidine?
Yes, it is an area of great concern
28
What is a nucleoside?
It is a base + sugar (ribose or deoxyribose) | e.g. gaunosine
29
What is a nucleotide?
It is a base + sugar + phosphate | e.g. dGMP, dGDP, dGTP
30
What are inhibitors of viral replication?
Most inhibitors of viral replication are either nucleoside or nucleotide analogues (NAs)
31
How do most nucleoside/nucleotide analogues (NAs) work?
They work by DNA/RNA chain termination
32
How are NAs classified?
They are RNA/DNA polymerase inhibitors
33
What are the most common antiviral agents?
Nucleoside/nucleotide analogues (NAs)
34
What is an example of a NA and how does it work?
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.
35
What is a NA against herpesviruses?
Acyclovir - acyclic guanosine analogue
36
What is acyclovir?
It is a NA against HSV-1, HSV-2
37
Is acyclovir approved for use by the FDA?
Yes, it was approved in 1982
38
What is the mode of action of acyclovir?
It is incorporated into the growing DNA strand by thymidine kinase and terminates viral DNA replication
39
What type of inhibitor is acyclovir?
It is a DNA polymerase inhibitor
40
What are 2 compounds that are related to acyclovir?
Ganciclovir and Famciclovir
41
What is ganciclovir active against?
Cytomegaloviruses
42
What is famciclovir active against?
Herpes and varicella zoster virus
43
What are the key targets for viral replication in HIV?
- Reverse transcriptase | - Novel viral enzyme
44
What is a NA against reverse transcriptase in HIV?
AZT, which is a thymidine analogue
45
What is AZT?
It is a NA, thymidine analogue, against reverse transcriptase in HIV
46
Is AZT approved for use by the FDA?
Yes, it was first licensed in 1987
47
What is the mode of action of AZT?
It is phosphorylated by host cell kinases and causes DNA termination
48
Does AZT have side effects?
Yes
49
What are more efficacious NA compared to AZT?
Lamivudine and Tenofovir
50
What is Truvada?
It is a NA against HIV consisting of tenofovir and emtricitabine
51
What is pre-exposure prophylaxis (PrEP) for HIV?
It is an anti-viral, Truvada, to be used for HIV-negative people at higher risk of developing HIV to prevent infection
52
What is tenofovir?
It is a nucleotide analogue of adenosine monophosphate
53
What is emtricitabine?
It is a nucleoside analogue of cytodine
54
Is Truvada available in Australia?
Yes, it was added to the PBS in 2018
55
What schedules is PrEp/Truvada available in?
It is available in two schedules: daily dosing and on-demand
56
How much does PrEp/Truvada reduce the risk of acquisition of HIV?
99%
57
How does Hepatitis B replicate?
It has a DNA genome with an RNA intermediate, requiring RNA transcriptase
58
Which drugs developed for HIV also work on Hepatitis B?
Lamivudine | Tenofovir
59
What are some licensed NA for Hepatitis B?
Lamivudine Adefovir Entecavir Tenofovir
60
Is resistance an issue with NA for Hepatitis B?
Yes with long-term use
61
What are the first line agents for Hepatitis B infection?
Entecavir and Tenofovir, as they have low resistance rates
62
Other than NAs, what are another type of agent that prevent viral replication?
Non-nucleotide RT inhibitors (NNRTIs)
63
What are 2 examples of NNRTIs for HIV?
Efavirenz and Rilpivirine | They are second generation
64
What is the mode of action of efavirenz and rilpivirine?
They bind to a unique binding site on one of the subunits of HIV reverse transcriptase (p66), causing a conformational change
65
What are efavirenz and rilpivirine?
They are second generation NNRTIs against HIV
66
Are efavirenz and rilpivirine substrates for p66?
No, but they can inhibit it by changing the conformation of the enzyme
67
Where do efavirenz and rilpivirine bind to on p66?
They bind to either dNTP binding site or the RT catalytic site
68
Is resistance an issue with efavrienz and rilpivirine?
Yes
69
What type of fidelity do reverse transcriptase and RNA polymerase have?
Poor fidelity
70
What are quasispecies?
They are new species of viruses that emerge through mutations occurring in viral replication
71
What is incomplete suppression?
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
What are 3 things that can cause incomplete suppression?
- Inadequate potency/drug levels - Inadequate adherence - Pre-existing resistant variants
73
How do resistant variants rise?
Selection of a minor quasispecies | Amplifaction by selection pressure
74
How does HIV develop resistance?
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
How do we overcome HIV resistance?
It can be overcome by combination anti-viral therapy
76
What is HAART?
Highly Active AntiRetroviral Therapy Now called ART Combination antiviral therapy
77
What amino acid changes are present in Lamivudine resistance?
L180M | M204V
78
What are proteases?
They are enzymes that cleave viral polypeptides
79
What was the first protease to have its 3D crystal structure determined?
HIV protease
80
What are 3 examples of HIV protease inhibitors?
Indinavir Darunavir Saquinavir
81
What is the mode of action of protease inhibitors?
Protease inhibitors are designed to fill binding pockets of the protease (7 aa peptides which mimic the substrate protein)
82
Are Hepatitis C protease and polymerase inhibitor approved for use?
Yes
83
What is interferon?
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
What is the mode of action of interferon?
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
What was interferon used for?
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
What are DDAs?
They are Direct Acting Antivirals developed for Hepatitis C in 2016
87
What are the targets for DDAs?
- Protease inhibitors - NS5A inhibitors - Polymerase inhibitors (Sofosbuvir)
88
What is NS3/4A inhibitor?
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
How many people in Australia are living with chronic Hepatitis C infection?
230,000
90
How many new cases of Hepatitis C in Australia each year?
10,000
91
How many people sough treatment and what was the outcome?
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
When did DDAs for Hepatitis C go on the PBS?
2016 with a greater than 95% cure rate and few SAEs
93
What is the significance of Hepatitis C infection?
399,000 deaths globally each year 583 deaths in Australia in 2017 66 liver transplants in Australia in 2017
94
What does neuraminidase do?
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
What is the mode of action of neuraminidase inhibitors?
They are sialic acid analogues that competitively inhibit the viral neuraminidase, this prevents the release of virus budding from the cell
96
What are 2 examples of neuraminidase inhibitors?
Relenza (Zanamivir) | Tamiflu (Oseltamivir)
97
What is Relenza (Zanamivir)?
It is a neuraminidase inhibitor that is taken as an inhalant (powder form)
98
What is Tamiflu (Oseltamivir)?
It is a neuraminidase inhibitor that is orally bioavailable, and comes in a tablet
99
When should Relenza (Zanamivir) and Tamiflu (Oseltamivir) be used?
They should be used within 2 days of illness
100
What do Relenza (Zanamivir) and Tamiflu (Oseltamivir) do?
They reduce the duration and symptoms of disease | They are also licensed for prophylactic use
101
What is the next generation of neuraminidase inhibitor being investigated?
Laninamivir

MIC3041 Medical Microbiology (11 decks)

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