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SEM 4: Medical Microbiology > Antivirals > Flashcards

Antivirals Flashcards

1
Q

Why do we need antivirals?

A
  • Viruses are quick killers such as Ebola, MERS and SARS
  • To control infection so no epidemics and pandemics
  • So chronic virus does not cause diseases such as cancer
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2
Q

What are the uses of antivirals?

A
  • Treatment of acute infection such as influenza, chickenpox, shingles and herpes infection.
  • Treatment of chronic infection such as HIV< HCV and HBV
  • Post-exposure prophylaxis
  • Pre-exposure prophylaxis
  • Prophylaxis for reactivated infections: when the pt is immunocompromised to prevent the reactivation of the virus
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3
Q

Post-exposure prophylaxis

A

When the patient is given antivirals after exposure to the virus to prevent infection

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4
Q

Pre-exposure prophylaxis

A

When the patient is given antivirals before exposure to the virus because they have high risk of getting an infection

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5
Q

What is selective toxicity?

A

This is the idea that an anti-viral drug needs to be able to harm the pathogen but not the host. There is a difference between the host and virus cells which allows for this. This is difficult for an anti-viral because the virus needs to be integrated into the host in order to replicate.

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6
Q

Why is it difficult to develop effective, nontoxic antiviral drugs?

A
  • Because viruses enter the cells via cellular receptors and so if you damage them or block you will be damaging the host receptors which may be needed for other processes.
  • Because viruses replicate inside the host using their genome so it is difficult to identify what is unique about the virus to attack.
  • Because some viruses are able to remain in the latent period, not replicating or expressing proteins so they are hard to attack.
  • Because the viruses have high mutation rates in the host
  • Because some viruses integrate their DNA with the host genome which means it is impossible to remove it from the host DNA.
  • It is important to consider when making an antiviral, the stages of infection, the cellular receptors used for the virus to enter, the viral enzymes which may be similar to the host enzyme.
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7
Q

Summarise the viral life cycle

A
  1. Virus enters the host cell via receptor mediated endocytosis or membrane fusion.
  2. The virus integrated with host DNA to form mRNA.
  3. At the ribosome the mRNA is changed to viral proteins.
  4. This is then assembled to form the new virus and the membrane will then lyse through the cell membrane.
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8
Q

Modes of action of anti-viral

A
  • Preventing virus adsorption into the host cell
  • Preventing penetration of the virus
  • Preventing viral replication
  • Preventing maturation of the virus to form provirus and proteins
  • Preventing viral release
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9
Q

Amantadine

A

Works by blocking the uncoating step in the virus once it enters the cell and forms an endosome - works on influenza A but toxicity on the host.

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10
Q

Acyclovir and Ganciclovir

A

Inhibit nucleic acid polymerisation and therefore inhibit the viral DNA from forming (from RNA for example) via working on the enzymes reverse transcriptase or viral DNA polymerase - works on HBV and HIV.

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11
Q

Ribavarin

A

Acts as an analogue for GMP and stops DNA replication

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12
Q

Zanamivir

A

Used to block the release of the virus from the cell - used as an anti-influenza drug

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13
Q

What enzymes can antivirals target?

A 
Some enzymes are only encoded by the virus and therefore, the drugs can target them and cause little damage to the host. 
These enzymes are: 
- Thymidine kinase in HSV, VZV, CMV
- Protease in HIV
- Reverse transcriptase in HIV
- DNA polymerases 
- Neuraminidase in influenza virus
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14
Q

Examples of Herpes virus

A

HSV, VZV, CMV and EBV

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15
Q

Symptoms of Herpes viruses

A
  • Mucocutaneous lesions on the skin which are blisters and ulcers such as those seen in chickenpox and shingles.
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16
Q

How are herpes viruses treated?

A

Using aciclovir antiviral which has a low toxicity and is an effective anti-viral

  • Can be givenorally, IV, or tropically.
  • Used as a treatment for HSV and VZV
  • Also as a prophylaxis for CMV and EBV
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17
Q

Other drugs that treat herpes virus

A
  • Ganciclovir - given orally or IV for CMV
  • Foscarnet - given IV or locally applied for CMV
  • Cidofovir - given IV for CMV
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18
Q

What is aciclovir?

A

An acyclic GTP analogue that means it loses some of the ribosome sugar so acts as a chain terminator and stops the continuation of the protein synthesis.
- On its own, it acts as a prodrug for the activation of acyclovir.

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19
Q

Action of aciclovir

A
  1. When taken, it is phosphorylated by thymidine kinase, an enzyme only present in the virus.
  2. It then gets di- and tri-phosphorylated by cellular GDP kinases and once it is in the tri-phosphate acyclovir form it is an active drug.
  3. It is now a competitive inhibitor for the viral DNA polymerase which competes for the stranded GTP and stops the stranded GTP and stops the viral polymerase from synthesising the viral genome.
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20
Q

How does aciclovir have a low toxicity?

A
  • It is a prodrug until activated in the infected cell by the viral enzyme.
  • It selectively inhibits the viral DNA polymerase and not the human DNA polymerase
21
Q

Why is acyclovir so safe?

A
  • HSV thymidine kinase has a very high affinity 100x for the drug compared to the cellular phosphokinase.
  • The drug has a high affinity (30x) to the viral DNA polymerase compared to the cellular DNA polymerase
  • The active drug is a highly polar which means it is difficult to leave or enter the cell whereas the prodrug is easily taken into the cell prior to phosphorylation so the drug accumulates when needed in an infected cell.
  • It is a DNA chain terminator.
22
Q

What is aciclovir used to treat?

A
  • HSV: treats encephalitis, genital infection and cause supress recurrent genital herpes
  • VZv: treat chickenpox, shingles and act as prophylazis of chickenpox
  • For CMV and EBV, it can only be used prophylaxis
23
Q

What is Ganciclovir?

A
  • Drug that can be used to treat CMV as acyclovir can only be used as prophylaxis for CMV -> By the time we are adults, we would’ve been exposed to CMV and have antibodies against it.
  • The reason aciclovir doesn’t work is because CMV does not code the enzyme thymidine kinase and therefore cannot activate the drug.
  • CMV codes UL97 kinase which is able to activate Ganciclovir
  • It is di- and tri-phosphorylated by cellular kinases and is not able to inhibit viral DNA polymerase
24
Q

When may a person be positive for active CMV?

A
  • When the infection is reactivated from latency
  • Congenital infection in newborn
  • Retinitis in immunosuppressed patients
25
Q

What is foscamet used for?

A
  • Used for CMV
  • Selectively inhibits viral DNA/RNA polymerases and reverse transcriptase like Ganciclovir
  • No reactivation is required as it is not a prodrug unlike Ganciclovir and Anciclovir
26
Q

Action of foscamet

A

Binds and blocks the enzymes, and is used in CMV patients who are immunocompromised.
Can also be used when a patient has Ganciclovir resistance CMV virus

27
Q

Cidofovir

A

A drug used for retinitis in HIV patients.
Prodrug that is phosphorylated by cellular kinases
Can be used against CMV however, it is nephrotoxic

28
Q

How does resistance to antivirals in Herpes virus occur?

A
  • Thymidine kinase mutants which means the prodrug is no longer activated, therefore drugs such as Aciclovir will not work. Those that don’t need phosphorylation will still be effective.
  • DNA polymerase mutants which means the drug can no longer bind and inhibit then. This is rare in immunocompetent because there are rarely any viral mutants in acute patients
29
Q

Summarise the mechanism of HIV

A
  1. The virus binds to the CD4 macrophage via the gp120 and the CORE proteins, which means it gets internalised and the viral genome is released after the viral uncoating.
  2. Reverse transcription occurs so the viral RNA becomes double stranded DNa
  3. Integration into the host chromosome the virus becomes provirus DNA
  4. Transcription of viral DNA to mRNA
  5. Translation of mRNA into viral proteins.
  6. Virus assembly and releasing by budding
  7. Maturation by the de-assembly of the polyproteins
30
Q

Types of Anti-HIV drugs

A
  • Anti-reverse transcriptase inhibitors
  • Protease inhibitors
  • Integrase inhibitors
  • Fusion inhibitors
    In reality, HIV is treated with HAART (highly active antiviral therapy) which is the combination of multiple drugs in order to prevent the emergence of resistance
31
Q

Two types of Anti-reverse transcriptase inhibitors

A
  • Nucleotide RT inhibitors - block reverse transcription by mimicking nucleotides
  • Non-nucleotide RT inhibitors - inhibit reverse transcription by binding to the allosteric site of the enzyme
32
Q

Protease inhibitors

A
  • There are multiple types, most viral proteases are not found in humans which makes them a good target as the drug will have low toxicity.
  • Proteases are needed for the maturation of the virus after assembly and therefore inhibitors stop the virus from becoming mature
33
Q

Integrase inhibitors

A

Integrase is needed for the crosslinking between the host and the viral genome and therefore by inhibiting the virus cannot replicate.

34
Q

Fusion inhibitors

A
  • Gp120 and gp41 biomimic lipopeptide prevent the fusion with the membrane and therefore the virus is not able to enter the cell.
  • In reality HIV is treated with HAART (highly active antiviral therapy) which the combination of multiple drugs in order to prevent the emerge of resistance.
35
Q

Action of nucleotide RT inhibitors

A
  1. Original AZT molecule that blocks reverse transcription acts as a synthetic analogue for nucleoside thymidine.
  2. It acts as a chain terminator so no more nucleotides can be incorporated into the synthesis of DNA chains.
  3. It acts as an analogue for dTP.
36
Q

Action of Non-nucleotide RT inhibitors

A

This is not a competitive inhibitor for the RT.

- Used in synergy with NRTIs which causes the 2 effects to be strong together

37
Q

How does resistance to antivirals occur?

A
  • When a single agent is used, it leads to rapid development of resistance.
  • The drug binding site is altered in structure by one amino acid substitution therefore the mutations rate is high.
  • The viral load is high.
  • Therefore, both of the above make you more likely to become resistance
  • Selection pressure and mutation frequency is high in HIV.
38
Q

What is a viral swarm?

A
  • The error rate in copying viral genome by reverse transcriptase enzyme is very high and there is a lack in proofreading.
  • Therefore all possible viral variants would be produced.
  • Hence why the combination of antivirals such as HAART is unlikely to become resistant to 3 drugs.
39
Q

What drugs are used against influenza?

A

Amantadine
Zanamivir
Oseltamivir

40
Q

Amantadine action

A

Inhibits the uncoating of the virus by blocking the M2 proteins, however this is rarely used because it is very toxic

41
Q

Zanamivir and oseltamivir

A

Inhibits the virus release from infected cell via inhibition of neuraminidase, therefore stops the chance of epidemic.
It works by preventing the virus budding and spreading to adjacent cells

42
Q

What is the influenza resistance to antivirals?

A
  • Resistance sometimes only requires single amino acid change
  • Seen in immunocompromised patients
  • Likely to be selected from among quasispecies during treatment
43
Q

Ribavirin

A
  1. This is a nucleotide analogue which blocks the RNA synthesis by inhibiting 5-monophosphate dehydrogenase which blocks the conversion of IMP to XMP.
  2. This stops GTP synthesis and therefore RNA synthesis.
  3. The drug needs to be phosphorylated first, so it is a prodrug.
  4. This is used to treat RSV and HepC.
44
Q

Action of HepC and direct acting antiviral (DAA)

A
  • Instead of depleting the pool of nucleotides, they inhibit the virus proteins involved in virus synthesis.
  • This is a new class of medication.
  • Acts to target specific steps in HCV viral life cycle.
  • This shortens the length of therapy, minimise side effecs, targets the virus itself, improve sustained virologic response rate.
  • Structural and non-structural proteins replicate and assemble new virions
45
Q

How do DAAs work?

A

1) Protease inhibitors: DAA that blocks the polyprotein processing (NS3/4) which means it cannot make the proteins needed to assemble the cell.
2) All the major HCV induces enzymes that are essential for HCV replication and are the potential drug targets

46
Q

Function of the NS5 gene

A

Produces proteins that are important in protein assembly therefore NS5A inhibitors prevent this.

47
Q

Functoin of the polymerase gene

A

Needed to make RNA but by using polymerase inhibitors it directly prevents the production of RNA.

48
Q

Combination of 3 DAA for HCV

A

Using a combination for the 3 DAA for HCV will produce a synergistic effect that leads to the eradication of the virus.

49
Q

Viruses that are not treatable

A 
Rabies 
Dengue 
Common cold viruses 
Ebola 
HPV 
Arboviruses 
There is no point of trying to make anti-virals as they are self-limiting infections that clear up anyway or there are vaccines against them.

SEM 4: Medical Microbiology (15 decks)

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