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Fundamentals of P > Mechanism of Antivirals > Flashcards

Mechanism of Antivirals Flashcards

1
Q

Why do we need anti-virals ?

A

Quick killers e.g. influenza; ebola; MERS; SARS

Slowly, progressive chronic disease leading to cancer
hepatitis B [350,000,000 carriers]
hepatitis C [200,000,000 carriers]
human papilloma viruses
[cervical cancer, second commonest cancer in women]

Human immunodeficiency virus (HIV)
[40 million infected]

Acute imflammatory e.g. herpes

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2
Q

Use of anti-virals

A

Treatment of acute infection
Influenza ; Chickenpox; herpes infections -(aciclovir)

Treatment of chronic infection:
HCV, HBV, HIV (numerous different agents)

Post-exposure prophylaxis and preventing infection:
HIV (PEP)

Pre-exposure prophylaxis: HIV (PrEP)

Prophylaxis for reactivated infection: e.g. in transplantation
CMV (ganciclovir, foscarnet)

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3
Q

Principles of Anti-Virals

as Therapeutic Agents - selective toxicity

A

Selective Toxicity
Due to the differences in structure and metabolic pathways between host and pathogen
Harm microorganisms, not the host
Target in microbe, not host (if possible)
Difficult for viruses (intracellular), fungi and parasites
Variation between microbes

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4
Q

Why is it so difficult to develop

effective, non-toxic anti-viral drugs ?

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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5
Q

Considerations in developing safe anti-viral agents

Can stages of infection be targeted?

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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6
Q

Virus Life Cycle

A
  1. recognition
  2. attachment
  3. penetration
  4. uncoating
  5. transcription
  6. protein synthesis
  7. replication
  8. assembly
  9. lysis and release
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7
Q

Modes of action of selected

anti-virals

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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8
Q

Discovery of virally encoded enzymes sufficiently different from human counterparts
e.g. and what do they act as

A

Discovery of virally encoded enzymes sufficiently different from human counterparts
e.g.

Thymidine kinase and HSV/VZV/CMV
Protease of HIV
Reverse transcriptase of HIV
DNA polymerases
Neuraminidase of influenza virus

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

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9
Q

Herpes viruses include:

A 
Herpes viruses include: 
Herpes simplex (HSV), 
Varicella Zoster Virus (VZV)
Cytomegalovirus (CMV)
Epstein-Barr virus (EBV)
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10
Q

Selective toxicity of acyclovir - explain what accounts for low toxicity

A

Requires 2 viral enzymes
= selectively activate ACV
= selectively inhibited

Accounts for low toxicity

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11
Q

Why is aciclovir 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

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12
Q

Aciclovir action in Herpes simplex

A

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

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13
Q

Aciclovir action in Varicella zoster virus

A

Varicella zoster virus
Treatment of chickenpox
Treatment of shingles
Prophylaxis of chickenpox

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14
Q

Aciclovir action in CMV/EBV

A

CMV/EBV

Prophylaxis only

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15
Q

Ganciclovir - use

A

Active for CMV
- reactivated infection or prophylaxis in organ transplant recipients
congenital infection in newborn
retinitis in immunosuppressed

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16
Q

Ganciclovir - compare with Aciclovir

A

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

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17
Q

Foscarnet - decribe action

A

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

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18
Q

Foscarnet - uses

A

used for CMV infection in the immunocompromised e.g. pneumonia in solid organ and bone marrow transplants.

May be used because of ganciclovir resistance (TK mutants)

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19
Q

Cidofovir - describe action

A

Cidofovir
Chain terminator - targets DNA polymerase
Competes with dCTP
Monophosphate nucleotide analog

Prodrug – phosphorylated by cellular kinases to di-phosphate
drug active against CMV; but MUCH MORE nephrotoxic

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20
Q

Cidofovir - used for

A

Treatment of retinitis in HIV disease

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21
Q

Resistance to anti-virals in Herpes viruses - list and describe mech.

A

Two main mechanisms

Thymidine Kinase mutants
DNA polymerase mutants

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

If occurs in DNA polymerase, all drugs rendered less effective

VERY RARE in immunocompetent patients (low viral load)

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22
Q

Structural features of HIV - list

A

Envelope protein, gp120
with transmembrane gp41

ds RNA genome

Membrane-
associated
matrix protein
Gag 17

Viral
envelope

Nucleocapsid protein
Gag p24

reverse transcriptase

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23
Q

Name the 7 steps in the life cycle of HIV

A

Attachment with binding
of viral gp120 via CD4 and CCRX

  1. Virus assembly and
    release by budding
  2. reverse transcription of RNA
    into dsDNA
  3. Transcription of viral genes
  4. Integration into host
    chromosome of
    proviral DNA
  5. Translation of viral mRNA
    into viral proteins
  6. maturation
24
Q

Anti-reverse transcriptase inhibitors - examples

A
  1. Anti-reverse transcriptase inhibitors

nukes -nucleoside/nucleotide RT inhibitors

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

25
Q

Protease inhibitors - examples

A
  1. Protease inhibitors - multiple types for HIV
26
Q

Integrase inhibitors - examples

A
  1. Integrase inhibitors – POL gene - protease, reverse transcriptase and integrase (IN)
    with the 3´end encoding for IN (polynucleotidyl transferase)
27
Q

Fusion inhibitors - examples

A
  1. Fusion inhibitors – gp120/41 - biomimetic lipopeptide
28
Q

HAART - purpose

A

Treatment - HAART

Combination of drugs to avoid resistance

29
Q

Nucleoside reverse transriptase (RT) inhibitors - nukes - describe action

A

Synthetic analogue of nucleoside thymidine –
when converted to tri-nucleotide by cell enzymes, it blocks RT by
- competing for natural nucleotide substrate dTTP
incorporation into DNA causing chain termination
Others ddI, ddC, d4T, and 3TC (2′,3′-dideoxy-3′-thiacytidine )

30
Q

Nucleoside reverse transriptase (RT) inhibitors - non-nukes - describe action

A

Non-competitive inhibitor of HIV-1 RT

Synergistic with NRTI’s such as AZT because of different mechanism

31
Q

Post-exposure prophylaxis for HIV

A

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

2x NRTIs + integrase inhibitor

32
Q

Pre-exposure prophylaxis for HIV

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
33
Q

NRTIs for HIV

A 
2 x NRTIs = 
Combination of Nucleoside RTIs
emtricitabine (guanosine analog) 
\+ 
tenofovir (adenosine analog)
34
Q

Resistance to anti-virals - describe cause

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

Mutation rate - high
Viral load – high
→ resistance

35
Q

Resistance to anti-virals - describe action

A

Selection pressure and mutation frequency
Increased mutation rate seen in HIV.

They form a quasispecies within an individual patient:-
A viral swarm

36
Q

Why do we use HAART for HIV

A

The 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

37
Q

Amantadine - describe use

A

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

38
Q

Zanamivir and Oseltamivir (Tamiflu) - describe action

A

Zanamivir and Oseltamivir (Tamiflu)
Inhibits virus release from infected cells via inhibition of neuraminidase
Oseltamivir –oral
Zanamivir- inhaled or IV - less likely for resistance to develop

39
Q

Anti’flu agents - Relenza - (zanamivir) and Tamiflu - (oseltamivir) = describe action

A

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

Neuraminidase inhibitors

40
Q

Influenza resistance to anti-virals - requires what

A

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

41
Q

Influenza resistance to anti-virals - describe example

A

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;

42
Q

Occupational Infection

Hazards - cause

A

Exposure prone incidents

Sharps, Splashes and blood-born viruses

43
Q

Occupational Infection

Hazards - prevention and management

A

Prevention - Universal Precautions

Management - Emergency Management of exposure prone incidents

44
Q

Post-exposure prophylaxis for Hep B - action

A

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

45
Q

Post-exposure prophylaxis for Hep C - action and +ves

A

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

46
Q

Post-exposure prophylaxis for Hep C - action

A 
HIV
	80% protection i.e. no sero-conversion
	must be FAST – hours
	antiviral drug treatment – 28 days
	2xNRTI + protease or integrase inhibitor
47
Q

Hepatitis C virus (HCV) - transmission

A

transmitted via blood – infectious (mother to baby)

48
Q

Hepatitis C virus (HCV) - amount of RNA

A

9.6 Kb RNA virus, enveloped

49
Q

Hepatitis C virus (HCV) - treatment

A

long incubation – 1 - 6 months
vaccination NOT available

early treatment facilitates resolution

50
Q

Ribavirin - define and describe action

A

Ribavirin
nucleoside analogue

lock 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

51
Q

Ribavirin - used for

A

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

52
Q

Hepatitis C virus (HCV)

and Direct-acting antivirals (DAAs) - use

A

acts to target specific steps in the HCV 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

53
Q

What is essential for HCV replication and explain why this is useful

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.

54
Q

DAA with different viral targets - effect

A

DAA with different viral targets, are synergistic in combinations

55
Q

Many viral infections with no effective therapies - list

A 
Many viral infections with no effective therapies
e.g. 
rabies
dengue
Common cold viruses
Ebola
HPV
Arbovirsues

Fundamentals of P (62 decks)

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