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Medical Microbiology > Mechanism of Antivirals > Flashcards

Mechanism of Antivirals Flashcards

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1
Q

What are the uses of antivirals?

A
  • Treatment of acute infection
  • Treatment of chronic infection
  • Post-exposure prophylaxis and preventing infection
  • Pre-exposure prophylaxis
  • Prophylaxis for reactivated infection
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2
Q

Outline the acute infections we can treat using antivirals

A

Influenza; Chickenpox; herpes infections are treated using aciclovir

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3
Q

Give examples of chronic infections treated using antivirals

A

HCV, HBV, HIV are treated with numerous different agents

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4
Q

Give examples of antiviral use in prophylaxis in reactivated infections

A

In immunosuppressed patients: e.g. in transplantation; CMV (ganciclovir, foscarnet)

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5
Q

What provides the selective toxicity of antivirals?

A

Selective toxicity due to differences in structure and metabolic pathways between host and pathogen
Enables harm to microorganisms, not host

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6
Q

Why is it so difficult to produce a non-toxic antiviral drug?

A

Difficult to achieve as viruses:

  • Enter cells using cellular receptors which may have other functions
  • Replicate inside cells
  • Take over host replicative machinery
  • Have high mutation rate
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7
Q

What is a major principle of antiviral agents?

A

Antivirals must be selective in their toxicity

i.e. exert their action only on infected cells

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8
Q

Why can it be difficult to target viruses in hosts?

A

Some viruses able to remain in latent state e.g. herpes, HPV
Some are able to integrate genetic material into host cells e.g. HIV

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9
Q

What factors must we consider when developing a safe antiviral drug?

A

We can target stages of viral infection however:

  • Cellular receptor may have other important function
  • Viral enzymes may be similar to host
  • Blocking cellular enzyme may kill cell
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10
Q

Describe the general life cycle of a virus

A
  1. Virus infects cell and attaches to membrane
  2. Internalisation via endocytosis / membrane fusion
  3. Uncoats and releases genome
  4. Genome replication and
  5. Reassembly of viral particles
  6. Budding and release out of cell
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11
Q

Describe the different mechanisms of action of selected antivirals

A
  • Preventing virus adsorption onto host cell
  • Preventing penetration
  • Preventing viral nucleic acid replication (nucleoside analogues)
  • Preventing maturation of virus
  • Preventing virus release
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12
Q

What is mantadine used to treat?

A
  • used to treat influenza infections
  • blocks viral uncoating mechanism (inhibits fusion of influenza virus to endosome)
  • associated toxicity
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13
Q

Which antivirals inhibit viral genomic replication from occurring?

A

Acyclovir, Ganciclovir, Ribavirin etc.
- HIV/AIDS AZT drugs

Inhibit nucleic acid polymerisation via RT / DNA pol inhibition

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14
Q

Describe the effects of Ribavarin

A

Ribavirin is an analogue of GTP - compromises viral genome replication as not enough precursors available

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15
Q

What is the mechanism of action of HIV Protease inhibitors?

A

HIV protease inhibitors block particle maturation and viral assembly

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16
Q

Outline the effect of Zanamivir on flu virus

A

Zanamivir blocks release of Flu virus - prevents infection of other cells; used more now

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17
Q

What component of viruses are good selective toxicity targets for antivirals?

A

Virally encoded enzymes sufficiently different from human counterparts

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18
Q

Outline the different Viral enzyme targets

A
  • Thymidine kinase + HSV / VZV / CMV
  • Protease of HIV
  • Reverse transcriptase of HIV
  • DNA polymerases
  • Neuraminidase of influenza virus
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19
Q

Why are viral enzymes good targets for antivirals?

A

Act as selective targets with minimal effect on host enzymes or processes

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20
Q

What is the consequence of Herpes virus infection?

A

Causes muco-cutaneous lesions

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21
Q

Which viruses are included within the herpes virus family?

A
  • Herpes simplex (HSV),
  • Varicella Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Epstein-Barr virus (EBV)
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22
Q

Which Herpes virus’ does Ganciclovir treat?

A

IV/oral

For CMV

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23
Q

When is Aciclovir administered?

A

IV/oral/topical
For HSV, VZV treatment/prophylaxis
CMV/EBV prophylaxis

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24
Q

What is the use of Cidofovir?

A

IV for CMV

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25
Q

When is Foscarnet used?

A

IV/local application

For CMV

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26
Q

Describe the mechanism of action of Aciclovir

A

GTP analogue; is a chain terminator - inserts into DNA to prevent polymerisation

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27
Q

How is aciclovir activated within host cells?

A

Aciclovir is phosphorylated by Viral Thymidine Kinase (TK)

Tri-phosphorylated by cellular kinases to become active

Substantially more in infected cells

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28
Q

What accounts for aciclovir’s low toxicity?

A

Aciclovir selective toxicity requires 2 viral enzymes
= to selectively activate ACV
= to selectively inhibit

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29
Q

Why does aciclovir have such high efficacy rates?

A

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

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

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30
Q

What makes aciclovir so efficient and safe?

A

Aciclovir triphosphate is a highly polar compound - difficult to leave or enter cells (but aciclovir is easily taken into cells prior to phosphorylation)

DNA chain terminator

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31
Q

When is aciclovir used for herpes simplex virus?

A

Treatment of encephalitis
Treatment of genital infection
suppressive therapy for recurrent genital herpes

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32
Q

What reason is aciclovir used for CMV?

A

Prophylaxis only

33
Q

Explain the use of aciclovir in VZV (varicella zoster virus)

A

Varicella zoster virus

  • Treatment of chickenpox
  • Treatment of shingles
  • Prophylaxis of chickenpox

Shingles (zoster)

34
Q

When is ganciclovir used?

A

Active for CMV

  • reactivated infection
  • prophylaxis in organ transplant recipients
  • congenital infection in newborn
  • retinitis in immunosuppressed
35
Q

Describe how ganciclovir structure helps inhibit CMV replication

A

Structurally similar to aciclovir
CMV does not encode TK but has UL97 kinase
Inhibits CMV DNA polymerase

36
Q

How does Foscarnet (anti-herpesVirus) agent work?

A

Selectively inhibits viral DNA/RNA polymerases and RTs
No reactivation required
Binds pyrophosphate binding site – a structural mimic

37
Q

When is Foscarnet used?

A

CMV infection; immunocompromised
e.g. pneumonia in solid organ + bone marrow transplants

May be used because of ganciclovir resistance (TK mutants)

38
Q

Describe the actions of Cidofovir

A

Chain terminator - targets DNA polymerase
Competes with dCTP
Monophosphate nucleotide analog
Prodrug – phosphorylated by cellular kinases to di-phosphate

39
Q

What is the use of Cidofovir?

A

Drug active against CMV; but MUCH MORE nephrotoxic

Treatment of retinitis in HIV disease

40
Q

How do Herpes Viruses become resistant to antivirals?

A

Two main mechanisms

  1. Thymidine Kinase mutants
  2. DNA polymerase mutants
41
Q

What are the consequences of TK mutant resistant viruses?

A

If occurs in TK, drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir)

42
Q

What is the consequence of antiviral resistance due to DNA pol mutants?

A

If occurs in DNA polymerase, all drugs rendered less effective

43
Q

Describe the structure of HIV

A

Enveloped virus with dsRNA genome, covered by capsid.

44
Q

Outline the 7 step life cycle of HIV

A
  1. Attachment with binding of viral gp120 via CD4/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
45
Q

What are the different anti-HIV drugs?

A
  1. Anti-reverse transcriptase inhibitors
  2. Protease inhibitors
  3. Integrase inhibitors
  4. Fusion inhibitors
46
Q

Outline the 2 types of anti-reverse transcriptase inhibitors

A
  • nukes - nucleoside/nucleotide RT inhibitors

- non-nukes - non-nucleoside RT inhibitors (allosteric)

47
Q

How is HIV treated?

A

Treatment - HAART

Combination of drugs to avoid resistance

48
Q

What are Nukes?

A

Nucleoside Reverse Transcriptase (RT) inhibitors - “Nukes”

Synthetic analogue of nucleoside thymidine

49
Q

How do nukes work against HIV?

A

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

Incorporated into DNA causing chain termination

50
Q

What are non-nukes?

A

e.g. Nevirapine
Non-competitive inhibitor of HIV-1 RT
Synergistic with NRTI’s such as AZT because of different mechanism

51
Q

Outline the post exposure prophylaxis for HIV

A

PEP – within 72 hours post exposure - take for 28 days.

2x NRTIs + integrase inhibitor

52
Q

What are the HIV pre-exposure prophylaxis?

A

PrEP – pre-exposure - blocks transmission
2x NRTIs (Truvada)
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

53
Q

Define what the 2x NRTIs are

A

2 x NRTIs = Combination of Nucleoside RTIs

emtricitabine (guanosine analog) + tenofovir (adenosine analog)

54
Q

How does antiviral resistance come about?

A

Use of single agents leads to rapid development of resistance

55
Q

Describe the structural changes that occur causing resistance

A

The drug binding site is altered in structure by as few as one amino acid substitution

56
Q

What factors increase antiviral resistance

A

Mutation rate - high
Viral load – high
= resistance

57
Q

How does HIV become resistant to antivirals

A

Selection pressure and mutation frequency

Increased mutation rate seen in HIV.
Forms quasispecies within individual patients:- A viral swarm

58
Q

Explain why sing a combination of antivirals reduces resistance

A

Error rate in copying viral genome by reverse transcriptase enzyme is 1 base per 10^4-5 incorporations; lacks proof reading capacity

So, for HIV with 10^9-10 viruses produced every day,

ALL possible viral variants would be produced

Hence use of combinations of antivirals e.g. HAART

59
Q

What common antivirals are used against Influenza?

A
  • Amantadine

- Neuraminidase Inhibitors: Zanamivir and Oseltamivir (Tamiflu)

60
Q

Explain how amantadine inhibits influenza virus

A

Inhibit virus uncoating by blocking influenza encoded M2 protein when inside cells and assembly of haemagglutinin
- Now rarely used

61
Q

Describe the mechanism of action of Zanamivir and Oseltamivir

A

Inhibits virus release from infected cells via inhibition of neuraminidase

62
Q

How are Zanamivir and Oseltamivir administered?

A

Oseltamivir –oral

Zanamivir- inhaled or IV - less likely for resistance to develop

63
Q

Describe the effects of neuraminidase inhibitors on influenza virus

A

Target + inhibit NA at highly conserved site (reduce chances of resistance via mutation)

Prevent release of sialic acid residues from cell receptor

Prevent virus budding, release + spread to adjacent cells

64
Q

How does influenza resistance to antivirals arise?

A

Resistance sometimes only requires single amino acid change - seen recently with swine flu (H1N1) and Tamiflu (oseltamivir)

Point mutation (H275Y; tyrosine replacing histidine)

Transmissible and virulent

65
Q

Which patients are most susceptible to influenza mutations?

A

Seen in immunocompromised patients; shed virus for weeks/months

Likely to be selected from among quasispcies during treatment
Remains sensitive to zanamivir

66
Q

What occupational infection hazards cause disease?

A

Exposure prone incidents - Sharps, Splashes and blood-born viruses

  • Hepatitis B
  • Hepatitis C
  • HIV
67
Q

How are exposure prone incidents prevented?

A

Prevention: Universal Precautions
Management: Emergency management of exposure prone incidents

68
Q

Describe the post-exposure prophylaxis of Hep B

A

Specific Hep B immunoglobulin (passive immunity)

+ vaccination within 48 hours (HBV treatment includes antivirals 3TC/NRTIs)

69
Q

What is the post-exposure prophylaxis of Hep C?

A

Interferon-γ + ribavarin (anti-viral) for 6 months
within first 2 months of exposure
90% cure rate - now direct acting antivirals

70
Q

What is the post-exposure prophylaxis of HIV?

A

80% protection i.e. no sero-conversion
Must be FAST – hours
antiviral drug treatment – 28 days

2xNRTI + protease or integrase inhibitor

71
Q

What is the HCV?

A

9.6 Kb RNA virus, enveloped; Flaviviridae family; identified in 1989 transmitted via blood – infectious (mother to baby)

72
Q

Describe the epidemiology of Hep C virus

A
  • Major chronic liver disease cause
  • ~170m people infected worldwide
  • Occupational risk groups; healthcare workers, needle-stick risk – 3% to sero-conversion; chronic carriage almost certain (85%)
  • Long incubation – 1 - 6 months
  • Vaccination NOT available
  • Prevalence in UK - ~6000 per year
    (95% are i/v drug users)
  • Early treatment facilitates resolution
73
Q

What is ribavarin?

A

Nucleoside analogue

Used to treat: RSV and HepC (in combination with pegylated interferon)

74
Q

Explain how ribavarin works

A

Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase –
this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)
and thereby stops GTP synthesis and, consequently, RNA synthesis

75
Q

What are DAAs?

A

Direct-acting antivirals (DAAs)
are a relatively new class of medication
act to target specific steps in HCV viral life cycle

76
Q

What are the benefits of using DAAs for HCV?

A

DAAs shorten length of therapy, minimize side effects, target the virus itself, improve sustained virologic response (SVR) rate.

77
Q

What are the DAA drug targets in HCV?

A

All the major HCV-induced enzymes - NS2-3 and NS3-4A proteases, NS3 helicase and NS5B RNA-dependent RNA polymerase (RdRp) are essential for HCV replication and are potential drug targets

78
Q

Outline viral infections with no current cure

A

Many viral infections with no effective therapies e.g.

  • rabies
  • dengue
  • Common cold viruses
  • Ebola
  • HPV
  • Arbovirsues

Medical Microbiology (15 decks)

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