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Microbiology and Immunology - SGUL (Sem 4) > Antivirals > Flashcards

Antivirals Flashcards

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1
Q

What antimicrobial drugs exits

A
  • Antibiotics
  • Anti-virals
  • Anti-fungals
  • Anti-protosoals
  • Anti-helminths
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2
Q

Why do we need anti-viral drugs

A
  • There are no or poorly effective vaccines for some viruses important to human health.
  • Not everyone can be administered a vaccine, even if that vaccine is effective.
  • Immune response to vaccine administration can take time (and several sequential administrations).
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3
Q

What are we currently using ant-viral drugs for

A
  • Treatment of acute infection - acyclovir
  • Treatment of chronic infection
  • Post-exposure prophylaxis and preventing infection
  • Pre-exposure prophylaxis
  • Prophylaxis for reactivated infection:
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4
Q

How do antiviral drugs work

A

Induces selective toxicity without harming infected cells

  • Target protein in virus, not infected cell
  • Due to the differences in structure and metabolic
    pathways between host and pathogen
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5
Q

What are the 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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6
Q

What are targets for anti-virals

A
  • Thymidine kinase and HSV/VZV/CMV
  • Protease of HIV
  • Reverse transcriptase of HIV
  • DNA polymerases
  • Neuraminidase of influenza virus
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7
Q

Why is it difficult to develop effective non-toxic antiviral drugs

A
  • Viruses use cellular proteins which may have other functions
  • Viruses must replicate inside cells – obligate intracellular parasites
  • Viruses take over the host cell replicative machinery
  • Viruses 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
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8
Q

What are often included with Herpes virus

A
  • Herpes simplex (HSV)
  • Varicella Zoster Virus (VZV)
  • Cytomegalovirus (CMV)
  • Epstein-Barr virus (EBV)
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9
Q

What antivirals can be used for herpes virus

A
  • Aciclovir
  • Ganciclovir
  • Foscarnet
  • Cidofovir
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10
Q

How can Acyclovir be used for treatment of herpes

A

Herpes simplex:

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

CMV/EBV:

  • Prophylaxis only

Varicella zoster virus:

  • Treatment of chickenpox
  • Treatment of shingles
  • Prophylaxis of chickenpox
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11
Q

Describe the mechanism of action of Aciclovir

A

Converted to active form by increasing the number of phosphate groups attached to it

Requires 2 viral enzymes:

  • selectively activate ACV
  • selectively inhibited

Resembles nucleotides and when used in viral DNA polymerase it causes chain termination

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12
Q

Why is acyclovir 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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13
Q

Describe the mechanism if action of ganciclovir

A

Active for CMV:

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

Structurally similar to aciclovir

CMV does not encode TK but has UL97 kinase

Inhibits CMV DNA polymerase

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14
Q

Describe how does foscarnet work

A
  • Selectively inhibits viral DNA/RNA polymerases and RTs
  • No reactivation is required
  • Binds pyrophosphate binding site – a structural mimic
  • 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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15
Q

Describe hoe does Cidofovir work

A
  • 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
  • Treatment of retinitis in HIV disease
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16
Q

How does resistance to herpes antivirals arise

A

They work in 2 main mechanisms:

  • Thymidine Kinase mutants
  • DNA polymerase mutants

If mutation occurs in TK, drugs not needing phosphorylation are still effective
(e.g. foscarnet, cidofovir)
- If it occurs in DNA polymerase, all drugs rendered less effective
- VERY RARE in immune competent patients (low viral load)

17
Q

What types of anti-HIV drugs are there

A
  • Anti-reverse transcriptase inhibitors - nucleoside/nucleotide RT inhibitors, non-nucleotide RT inhibitors (allosteric)
  • Protease Inhibitors - Multiple types
  • Integrase inhibitors – POL gene, protease, reverse transcriptase and integrase (IN) with the 3´end encoding for IN (polynucleotidyl transferase)
  • Fusion inhibitors - gp120/41, biomimetic lipopeptide

Treatment - Highly Active Anti Retroviral Therapy HAART Combination of drugs to avoid resistance

18
Q

How does Nucleoside reverse transcriptase (RT) inhibitors work

A

It is 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
19
Q

How does Non-nucleoside reverse transcriptase inhibitors work

A

Non-competitive inhibitor of HIV-1 RT

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

20
Q

What is given for post-exposure for HIV

A
  • within 72 hours post-exposure
  • take for 28 days
  • 2x NRTIs + integrase inhibitor
21
Q

What is given for Pre-exposure for HIV

A
  • pre-exposure - blocks transmission
  • 2x NRTIs (Truvada) two tablets 2
  • 24 hours before sex, one 24 hours after intercourse and a further tablet 48 hours after intercourse
  • called ‘on-demand’ or ‘event-based’ dosing
22
Q

What is in the 2x NRTI treatment

A

Combination of Nucleoside RTIs emtricitabine (guanosine analog) and tenofovir (adenosine analog)

23
Q

How does resistance to anti-virals come about

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
  • When mutation rate and viral load are high there is increased resistance to antivirals
24
Q

How do viral quasispecies come about

A
  • Selection pressure and mutation frequency
  • Increased mutation rate seen in HIV
  • They form a quasispecies within an individual patient: A viral swarm
  • Reverse transcriptase lacks proofreading ability.
  • All possible viral variants would be produced, hence the use of a combination of antivirals, e.g: HAART
25
Q

Describe how amantadine works against influenza virus

A

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

Now rarely used

26
Q

Describe how does Zanamivir and Oseltamivir (Tamiflu)
work against influenza virus

A
  • Inhibits virus release from infected cells via
    inhibition of neuraminidase
  • Oseltamivir - oral
  • Zanamivir - inhaled or IV, less likely to develop resistance
27
Q

How do neuraminidase inhibitors work

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
28
Q

How does ant-viral resistance occur in influenza

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 immunocompromise patients; shed virus for weeks/months
  • Likely to be selected from among quasispcies during treatment
  • Transmissible and virulent
  • Remains sensitive to zanamivir
29
Q

What is Hepatitis C

A
  • 9.6 Kb RNA virus, enveloped; Flaviviridae family; identified in 1989
  • transmitted via blood – infectious (mother to baby)
  • increasingly common – high risk groups – drug users 20% +ve; – needles (sex?)
  • major cause of chronic liver disease
  • 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
30
Q

How does the nucleoside analogue ribavirin work

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

Has to be activated by being phosphorylated with the help of ATP

31
Q

How do Direct-acting antivirals work against hepatitis C

A
  • relatively new class of medication
  • 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
  • HCV - first chronic viral infection to be cured without IFN or ribavirin.
32
Q

What is seen as an occupational injection hazards

A
  • Exposure-prone incidents
  • Sharps, splashes and blood-borne viruses

Prevention - Universal precautions
Management - Emergency management of exposure prone incidents

33
Q

What is given as post-exposure prophylaxis treatment for Hep B

A

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

34
Q

What is given as post-exposure prophylaxis treatment for Hep C

A

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

35
Q

What is given as post-exposure prophylaxis treatment for HIV

A

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

36
Q

What are classified as incurables

A
  • rabies
  • dengue
  • Common cold viruses
  • Ebola
  • HPV
  • Arbovirsues
  • “Pathogen X”

Microbiology and Immunology - SGUL (Sem 4) (30 decks)

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