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Medical Microbiology > Mechanism of Antiviral > Flashcards

Mechanism of Antiviral Flashcards

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1
Q
  1. Which pathogens are we fighting against when we use :
    - Antibiotics
    - Antivirals
A

Antibiotics = fighting against bacteria

Anti-virals = fighting against viruses

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2
Q
  1. Why is it important we have anti-virals?
A
  • Prevent epidemics ( eg influenza,ebola)
  • Some viruses lead to cancer (eg Hep B/C and human papilloma virus)
  • To treat acute inflammatory infections (herpes)
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3
Q
  1. What are some (3) acute infections we can treat using aciclovir?
A
  • Influenza
  • Chickenpox
  • Herpes
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4
Q
  1. There are numerous agents we can use to treat chronic infections. List three examples of viral chronic infections?
A
  • HCV
  • HBV
  • HIV
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5
Q
  1. What is the difference between pre-exposure prophylaxis and post-exposure prophylaxis ?
A

Pre-exposure prophylaxis = given to PREVENT infection eg if there’s a high chance someone will be exposed to HIV they would be given a HIV PrEP

Post-exposure prophylaxis = after someone has been exposed to an infection, important its given within 72 hours (preferably 24hrs) eg HIV PEP

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6
Q
  1. What type of antiviral could you use for a reactivated infection?
A

You can use a prophylaxis

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7
Q
  1. Give some examples of when you would have a reactivated infection and give examples of the specific drugs you could use to treat these?
A

Transplation/Immunosuppression/Cancer are some examples of why you may get re-infected.
For eg reactivated infection of CMV (shingles in adults) would be treated by Ganciclovir or Foscarnet

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8
Q
  1. What is the principle of selective toxicity that we want antivirals to achieve ?
A

We want anti-virals to achieve this idea of selective toxicity - harm the microorganisms NOT the host.

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9
Q
  1. What makes it possible for selective toxicity
A

Possible if :

  • Target of the anti viral is inside the microbe, not the host
  • There are differences and structure and metabolic pathways between host and the pathogen
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10
Q
  1. Why is it so difficult to develop effective, non-toxic anti-viral drugs ?
    Give 7 reasons
A

Viruses enter cells using cellular receptors which may have other functions

Viruses must replicate inside cells – obligate intracellular parasites

Viruses take over the host cell replicative machinery

Virsues have high mutation rate - quasispecies

Anti-virals must be selective in their toxicity
i.e. exert their action only on infected cells

Some viruses are able to remain in a latent state e.g. herpes, HPV

Some viruses are able to integrate their genetic material into host cells e.g. HIV

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11
Q
  1. Briefly summarise the virus life cycle?
A
  1. Virus recognises the cell and attaches to the membrane and gets internalised by either :
    - Endocytosis
    - Membrane Fusion
  2. Once the virus is inside, it uncoats and releases its genome
  3. Genome replicates itself using cells machinery
  4. Virus makes mRNA–> goes to ribosome —> viral protein
  5. Viral reassembles itself by either :
    - Budding through the membrane
    - Cell Lysis
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12
Q
  1. What are some considerations when making an antiviral that is specifically targeting different stages of infection
A

Cellular receptor may have other important function

Viral enzymes may be very similar to host

Blocking cellular enzyme may kill cell

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13
Q
  1. What are some different modes of actions of 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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14
Q
  1. What is Amantadine ?
    - Which virus do we use it for
    - How does it work
A

Amantadine’s mode of action is preventing uncoating. Does this by blocking low pH endosome dependant on coating M2 Protein
Effective for Influenza A

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15
Q
  1. What do :
    -Acyclovir
    -Ganciclovir
    -Ribavarin
    use as a mode of method?
A

They inhibit nucleic acid polymerisation –> target reverse transciptases or DNA polymerases

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16
Q
  1. How does Ribavarin specifically work?
A

Its an analogue of Guanosine , it compromises genome replication

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17
Q
  1. How cam we use protease inhibitors to target HIV?
A

As we cant make viral proteins , it blocks particle maturation and assembly of the virus

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18
Q
  1. What is Zanamivir?
    what is its mode of action
    which virus does it target
A

Blocks release of virus from the cell

Targets influenza

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19
Q
  1. One main mode of action of antivirals is targeting virally encoded enzymes that sufficiently different from human counterparts, what are some examples of this?
A 
Thymidine kinase and HSV/VZV/CMV
Protease of HIV
Reverse transcriptase of HIV
DNA polymerases
Neuraminidase of influenza virus-> stops virus from budding
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20
Q
  1. What virus causes muco-cutaneous lesions ?
A

Herpes Simplex

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21
Q
  1. Which virus causes chickenpox and Shingles (in adult)
A

Varicella Zoster Virus

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22
Q
  1. There are 8 types of Herpes, list any 4 of those 8?
A 
Herpes simplex type I (HSV-1).
Herpes simplex type II (HSV-2).
Varicella-zoster virus (VZV/HHV-3).
Epstein-Barr virus (EBV/HHV-4).
Cytomegalovirus (CMV/HHV-5).
Herpes virus type 6 (HBLV/HHV-6).
Herpes virus type 7 (HHV-7).
Kaposi's sarcoma herpes virus (KSHV/HHV-8).
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23
Q
  1. Which type of Herpes is aciclovir good at treating and which herpes can we use aciclovir as a prophylaxis for?
A

We can use it for HSV and VZV treatment

We can it as a prophylaxis for CMV and EBV

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24
Q
  1. Seeing as we cant use aciclovir for treatment of CMV , which three drugs can we use as treatment of CMV?
A
  • > Ganciclovir
  • > Foscarnet
  • > Cidofovir
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25
Q
  1. Explain the mechanism of aciclovir?
A

Aciclovir is an analogue of GTP ( missing a 3’OH group so that when incorporated into DNA it acts as chain terminator )

  1. Aciclovir activated by phosphorylation by viral thymidine kinase (this is encoded by the genome of the virus)
  2. Aciclovir is now stable but gets di- and tri- phosphorylated by Cellular GDP kinases
  3. Now its in the active drug form- a competitive inhibitor
  4. Competes with GTP for Viral DNA polymerase
  5. Once incorporated , acts as chain terminator and stops viral genome binding to Viral DNA polymerase
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26
Q
  1. In which 2 ways does Aciclovir achieve low toxicity to the host?
A
  1. Selectively activated in cells that are infected- mainly activated by viral thymidine kinase but only infected cells have thymidine kinase. Unlikely for drug to be activated in uninfected cells
  2. Once phosphorylated by cellular kinase – product which has selective toxicity to the viral DNA polymerase is 30x more active against viral polymerases than host polymerases.
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27
Q
  1. Give four reasons why aciclovir is so effective and safe?
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

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

28
Q
  1. What specifically can Aciclovir treat in the Herpes Simplex Virus?
A

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

29
Q
  1. What specifically can Aciclovir treat in the Varicella Zoster Virus?
A

Treatment of chickenpox
Treatment of shingles
Prophylaxis of chickenpox–>protect babies
Shingles

30
Q
  1. What is the mechanism for how Ganciclovir can treat CMV?
A

Ganciclovir (structurally similar to aciclovir) phosphorylated by UL97 kinase, and then di and tri by cellular kinases, and then competes for the natural substrate for DNA polymerase , blocks virus making its own genome

31
Q
  1. Why can aciclovir not treat CMV effectively?
A

CMV doesn’t encode a TK needed to activate aciclovir

32
Q
  1. CMV causes mild flu like symptoms and we usually have antibodies made for it and its not that harmful USUALLY. In which case would CMV be an issue
A
  • > A reactivated infection
  • > Congenital infections in newborn
  • > Immunosuppressed (can lead to retinitis).
  • > Organ Transplant Recipients (should be given prophylaxis)
33
Q
  1. How does Foscarnet work and which virus is it used to treat?
A

Selectively inhibits viral DNA/RNA polymerases and RTs
No reactivation required (it’s not a pro drug)
Binds pyrophosphate binding site – a structural mimic
used for CMV infection in the immunocompromised
e.g. pneumonia in solid organ and bone marrow transplants.

34
Q
  1. Why might we use Foscarnet over Ganciclovir?
A

Some viruses may develop resistance to ganciclovir by having a mutation that effects the UL97 kinase
As Foscarnet doesn’t require activation by UL97 kinase - it can work

35
Q
  1. How does Cidofovir work and which virus is it used to treat?
A

Similar to aciclovir , it is a monophosphate nucleotide analogue for dCTP and is a chain terminator that targets DNA polymerase. It is a pro drug and therefore needs to be activated (by phosphorylation of cellular kinases)

It is used in treatment for CMV (however it is much more nephrotoxic)
It can also be used as treatment of retinitis in HIV disease

36
Q
  1. What are the two main mechanisms by which herpes viruses can become resistant to antivirals?
A

Thymidine Kinase mutants

DNA polymerase mutants

37
Q
  1. Which two drugs are still effective in TK mutant herpes virus?
A

(As they don’t need activation)

  1. Foscarnet
  2. Cidofovir
38
Q
  1. Which drugs work at the same effectiveness if there is a mutation in the DNA polymerase?
A

none!

All drugs are less effective

39
Q
  1. Which type of patients is resistance to anti-virals rare in?
A

VERY RARE in immune competent patients (low viral load)

40
Q
  1. Briefly explain the structure of HIV?
A

From inside (core) to outside (surface)

  • > ds RNA genome
  • > Reverse Transcriptase
  • > Nucleocapsid protein eg Gag p24
  • > Membrane associated matrix protein Gag 17
  • > Viral Envelope
  • > Envelope protein (gp120 and gp41)
41
Q
  1. Name the 7 steps in the life cycle of HIV?
A
  1. Attachment with binding of viral gp120 via CD4 and 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
42
Q
  1. What are four modes of method for Anti-HIV drugs?
A
  1. Anti-reverse transcriptase inhibitors
  2. Protease Inhibitors
  3. Integrase Inhibitors
  4. Fusion Inhibitors
43
Q
  1. What are the two types of anti-reverse transcriptase inhibitors
A

2 types:

  1. Nukes = Block RT enzymes by mimicking nucleotides and nucleosides
  2. Non-Nukes = Inhibit RT through allosteric mechanisms
44
Q
  1. How does protease inhibitors work?
A

Proteases produced by viral genome are essential for viral assembly and maturation, If we block these. The virus cant assemble . Very potent . Proteases are usually unique to virus – so drug wont have effect on host toxicity

45
Q
  1. How do integrase inhibitors work?
A

Integrase inhibitor- genome integrates into host DNA via integrase, POL gene encodes for 3 separate components – one of them Is integrase (allows viral DNA –> host DNA) so anti viral needs to target this integrase enzyme. Virus cant be permanently established into host germ line

46
Q

46.How do fusion Inhibitors work?

A

Fusion into membrane to allow virus enters via gp120/41 , fusion inhibitor block infection of cell. Biomimetic lipopeptides of that process and interrupt gp120/41 fusion into the membrane

47
Q
  1. What type of therapy do we use to treat HIV?
A

combination of drugs (to prevent resistance) HAART (highly active anti viral therapy)

48
Q
  1. How do Nucleoside Reverse Transciptase (RT) inhibitors “Nukes” work, specifically Zidovudine?
A

ZIdovudine blocks the RT of HIV
Its a synthetic analogue of nucleoside thymidine ( where you would usually have a 3’OH group, you have an azido group)
It needs to get converted to tri-nucleotide by cell enzymes and then it competes for natural nucleotide dTTP and the gets incorporated into DNA and causes chain termination= blocks RT

49
Q
  1. How do Non-Nucleoside Reverse Transcriptase Inhibitors “Non-Nukes” work? ,specifically Nevirapine?
A

(NOT an analogue or to do with chain termination)
It acts as a non-competitive inhibitor of HIV-1 RT
Synergistic with NRTI’s such as AZT because of different mechanism

50
Q
  1. After exposure to HIV, how long do you have to take a post-exposure prophylaxis and what do they consist of?
A

Within 72 hours post exposure
Have to take them for 28days
Consist of 2x NRTIs (nukes) and an integrase inhibitor

51
Q
  1. Before exposure to HIV, how long do you have to take a pre-exposure prophylaxis and what do they consist of?
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
52
Q
  1. Specifically which nukes can be used as a pre-exposure prophylaxis for HIV?
A 
2 x NRTIs = 
Combination of Nucleoside RTIs
emtricitabine (guanosine analog) 
\+ 
tenofovir (adenosine analog)
53
Q
  1. Why is there high resistance to anti-virals used in HIV?
A

Use of single agents leads to rapid development of resistance

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

Selection pressure and mutation frequency

Increased mutation rate seen in HIV- lacks proof reading capacity

54
Q
  1. HIV produces a quasispecies within a patient, what is this?
A

a population structure of viruses with a large numbers of variant genomes (related by mutations).
“ A viral swarm”

55
Q
  1. How does the drug Amantadine work to treat Influenza Virus
    Why do we not use it so much nowadays
    ?
A

Amantadine inhibits the virus uncoating by inhibiting the influenza virus uncoating by blocking the encoded M2 protein and the assembly of haemagglutinin

its rarely used nowadays as there are too many side effects

56
Q
  1. How do Tamiflu (oseltamivir) and Relenza (zanamivir) work for influenza virus?
A

it only works in the first 24 hrs of being exposed
Works by inhibiting virus release from infected cells via inhibition of neuraminidase :

target and inhibit NA at highly conserved site (reduce chances of resistance via mutation)

prevent release of sialic acid residues from the cell receptor

preventing virus budding and release and spread to adjacent cells

57
Q
  1. Why do we get influenza resistance to anti-virals?
A

Resistance sometimes only requires a single amino acid change - seen recently with swine flu (H1N1) and Tamiflu (oseltamivir)
Point mutation (H275Y; tyrosine replacing histidine)
Seen in immunocompromised patients; shed virus for weeks/months
Likely to be selected from among quasispcies during treatment
Transmissible and virulent
Remains sensitive to zanamivir;

58
Q
  1. What are some incidents that might occur at work eg lab/hospital that are exposure prone?

How can we prevent these incidents ?

A

Sharps
Splashes
Blood-born viruses

Prevention - Universal Precautions

59
Q
  1. What type of post exposure prophylaxis should be taken after Hep B exposure ?
A

specific Hep B immunoglobulin (passive immunity) + vaccination
within 48 hours (HBV treatment includes antivirals 3TC/NRTIs)

60
Q
  1. What type of post exposure prophylaxis should be taken after Hep C exposure ?
A

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

61
Q

61.What type of post exposure prophylaxis should be taken after HIV exposure ?

A

80% protection i.e. no sero-conversion
must be FAST – hours
antiviral drug treatment – 28 days
2xNRTI + protease or integrase inhibitor

62
Q
  1. The following questions are about Hep C Virus:
    - > How is it transmitted?
    - >Which disease can it cause?
    - > Is there a vaccination available?
A

Transmitted by blood (mother–> baby) (needles)
Major cause of chronic liver disease
No vaccination present

63
Q
  1. What can we use Ribavarin to treat and how?
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

Treat: RSV and HepC (in combination with pegylated interferon)

64
Q
  1. What are Direct-acting antivirals (DAAs) ?
A

relatively new class of medication

acts to target specific steps in the HCV(hep c virus) viral life cycle

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

structural and non-structural proteins - replicate and assemble new virions

HCV - first chronic viral infection to be cured without IFN or ribavirin.

65
Q
  1. List some examples of the major HCV-induced enzymes which can be used as drug targets?
A

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.

66
Q
  1. Not all viruses are treatable, give 3 examples of viruses that are not treatable ?
A 
Any 3 out of :
rabies
dengue
Common cold viruses
Ebola
HPV
Arbovirsues

Medical Microbiology (15 decks)

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