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lolmyi > Mechanisms of action of antivirals > Flashcards

Mechanisms of action of antivirals Flashcards

1
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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2
Q

What are the current use of anti-viral drugs?

A 
→Treatment of acute infection
→Treatment of chronic infection
→Post-exposure prophylaxis and preventing infection-HIV
→Pre-exposure prophylaxis
→Prophylaxis for reactivated infection
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3
Q

Examples of acute infections treated with anti-viral drugs

A

→Influenza
→Chickenpox
→herpes infections

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4
Q

What drug is used to treat influenza, chickenpox, and herpes?

A

→aciclovir

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5
Q

What chronic infections are treated with antivirals?

A

→HCV,
→HBV,
→HIV

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6
Q

What viral disease cab be reactivated and what drug is used to treat it?

A

→CMV

→ganciclovir

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7
Q

How do we induce selective toxicity?

A

→Target protein in virus, not infected cell

→Due to the differences in structure and metabolic pathways between host and pathogen

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8
Q

Summarise virus life cylce

A 
→recognition
→attachment
→penetration
→uncoating
→transcription
→protein synthesis
→replication
→assembly
→lysis and release
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9
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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10
Q

What is the mechanism of action of Amantadine?

A

→blocks low pH endosome dependent on coating M2 protein

→influenza A

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11
Q

What doe HIV protease inhibitors work?

A

→block protein synthesis

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12
Q

What is the mechanism of action of Zanamivir?

A

→blocks viral release

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13
Q

What is the mechanism of action of viral interferons?

A

→blocks viral mRNA translation

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14
Q

What is the mechanism of action of AZT?

A

→blocks HIV reverse transcriptase to prevent formation of dsDNA provirus from the HIV RNA genome

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15
Q

What do acyclovir, ganciclovir, and ribavarin have in commom?

A

→inhibit nucleic acid polymerisation

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16
Q

What are some commonly used anti-viral drugs targets?

A

→Thymidine kinase and HSV/VZV/CMV

→Protease of HIV

→Reverse transcriptase of HIV

→DNA polymerases

→Neuraminidase of influenza virus

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17
Q

Why is it so difficult to develop

effective, non-toxic anti-viral 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

→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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18
Q

What virus causes these muco-cutaneous lesions ?

A

→Herpes viruses

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19
Q

What are the different herpes viruses?

A

→Herpes simplex (HSV),
→Varicella Zoster Virus (VZV)
→Cytomegalovirus (CMV)
→Epstein-Barr virus (EBV)

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20
Q

What does ganciclovir treat?

A

→IV/oral

→For CMV

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21
Q

What does foscarnet treat?

A

→IV/local application

→For CMV

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22
Q

What does cidofovir treat?

A

→IV for CMV

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23
Q

How is aciclovir used to treat CMV/EBV?

A

→Prophylaxis only

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24
Q

How is aciclovir used to treat herpes simplex?

A

→Treatment of encephalitis

→Treatment of genital infection

→suppressive therapy for recurrent genital herpes

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25
Q

How is aciclovir used to treat VZV?

A

→Treatment of chickenpox

→Treatment of shingles

→Prophylaxis of chickenpox

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26
Q

How does aciclovir work?

A

→Activated by Thymidine kinase by increase number of phosphate residues in aciclovir

→Looks like DNA base so viral DNA incorporates acyclovir

→chain termination

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27
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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28
Q

What is the mechanism of action of ganciclovir?

A

→Inhibits CMV DNA polymerase

29
Q

What structure is acyclovir similar to?

A

→guanosine

30
Q

What are diseases ganciclovir used for?

A

→reactivated infection or prophylaxis in organ transplant recipients

→congenital infection in newborn

→retinitis in immunosuppressed

31
Q

What is ganciclovir similar to?

A

→aciclovir

32
Q

What does CMV encode which is similar to TK in function?

A

→has UL97 kinase

33
Q

When might foscarnet be used?

A

→because of ganciclovir resistance (TK mutants)

34
Q

Describe mechanism of action of foscarnet

A

→Selectively inhibits viral DNA/RNA polymerases and RTs

→No reactivation required

→Binds pyrophosphate binding site – a structural mimic

35
Q

What virus is foscarnet used to treat?

A

→CMV infection in the immunocompromised

36
Q

How does cidoforvir work?

A

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

37
Q

What type of drug is cidofovir?

A

→prodrug

→phosphorylated by cellular kinases to di-phosphate

38
Q

What is cidofovir used to treat?

A

→drug active against CMV; but MUCH MORE nephrotoxic

Treatment of retinitis in HIV disease

39
Q

What are the two main ways viruses become resistant to antivirals?

A

→Thymidine Kinase mutants

→DNA polymerase mutants

40
Q

What can be done if resistance occurs in Thymine Kinase?

A

→drugs not needing phosphorylation are still effective (e.g. foscarnet, cidofovir)

41
Q

What happens if resistance occurs in DNA polymerase?

A

→all drugs rendered less effective

42
Q

What are the structural features of HIV?

A 
→Envelope protein, gp120 
with transmembrane gp41
→Membrane- 
associated 
matrix protein
Gag 17
→Nucleocapsid protein 
Gag p24
→ds RNA genome
→Viral 
envelope
→Nucleocapsid protein 
Gag p24
→ds RNA genome
43
Q

Describe the life cycle of HIV

A 
→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
→. Virus assembly and 
release by budding 
→7. maturation
44
Q

What are the types of anti-HIV drugs?

A

→Anti-reverse transcriptase inhibitors
→Protease inhibitors
→Integrase inhibitors
→ Fusion inhibitors- gp120/41 - biomimetic lipopeptide

→Highly Active Anti Retroviral Therapy HAART

45
Q

What are the two types of anti-reverse transcriptase inhibitors?

A

→nucleoside/nucleotide RT inhibitors

→ non-nucleotide RT inhibitors (allosteric)

46
Q

How do nucleoside reverse transcriptase inhibitors work?

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

47
Q

How do non-nucleoside reverse transcriptase inhibitors work?

A

→Non-competitive inhibitor of HIV-1 RT
→Do not look like DNA bases
Gets incorporated into viral DNA by RT- terminates production of new viral DNA
→Synergistic with NRTI’s such as AZT because of different mechanism

48
Q

What are post exposure prophylaxis for HIV?

A

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

2x NRTIs + integrase inhibitor

49
Q

What are pre- exposure prophylaxis for HIV?

A

→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

50
Q

What two factors lead to viral resistance to drugs?

A

→Mutation rate - high

→Viral load – high

51
Q

What events lead to viral swarm?

A

→Selection pressure and mutation frequency

→Increased mutation rate seen in HIV.

→They form a quasispecies within an individual patient

52
Q

How does amantadine work?

A

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

53
Q

How do zanamivir and Oseltamivir work?

A

→Inhibits virus release from infected cells via inhibition of neuraminidase

54
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

55
Q

What is influenza still sensitive to?

A

→zanamivir

56
Q

How is Hep C commonly transmitted?

A

→via blood – infectious (mother to baby)

57
Q

What is Hep C a major cause of?

A

→chronic liver disease

58
Q

What is the incubation length of Hep C?

A

→1 - 6 months

59
Q

What family of viruses does Hep C belong to?

A

→enveloped; Flaviviridae family

60
Q

How does ribavirin?

A

→Block RNA synthesis by inhibiting inosine 5’-monophosphate (IMP) dehydrogenase –

→blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)

→thereby stops GTP synthesis and, consequently, RNA synthesis

61
Q

What does ribavirin treat?

A

→RSV
→HepC
→combination with pegylated interferon

62
Q

What are advantages of direct-acting antivirals?

A

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

63
Q

Describe the mechanism of action of direct-acting antivirals

A

→block replication complex formation assembly

64
Q

What are the major Hep C induced viruses?

A

→NS2-3 and NS3-4A proteases

→NS3 helicase and NS5B

65
Q

What is the post-exposure prophylaxis for Hep B?

A

→specific Hep B immunoglobulin (passive immunity)
→+ vaccination
→within 48 hours

66
Q

What is the post-exposure prophylaxis for Hep C?

A

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

67
Q

What is the post-exposure prophylaxis for HIV?

A

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

68
Q

Examples of the incurables viruses

A 
→rabies
→dengue
→Common cold viruses
→Ebola
→HPV
→Arbovirsues

lolmyi (31 decks)

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