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Microbiology and immunology > Mechanism of action of antivirals > Flashcards

Mechanism of action of antivirals Flashcards

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Biology 101 flashcards
1
Q

What are anti-viral drugs currently used to treat?

A

Treatment of acute infection

  • Influenza, chickenpox, herpes infections – aciclovir

Treatment of chronic infection

  • HCV, HBC, 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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2
Q

What is the virus life cycle?

A

Recognition and attachment gets virus into cell

Penetration and uncoating, allow release of viral genome into cytoplasm or nucleus

Replication via transcription and protein synthesis, gets new viral DNA or RNA

These are assembled into new viruses

Released

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3
Q

What is the modes of action of selected anti-virals?

A

Prevent 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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4
Q

What can be used as selective targets within viruses and have minimal effect on host enzymes/processes?

A

Virally encoded enzymes sufficiently different from human counterparts e.g

Thymidine kinase and HSV/VZV/CMV

Protease of HIV

Reverse transcriptase of HIV

DNA polymerase

Neuraminidase of influenza virus

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5
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 to do this

And Viruses have high mutation rate – quasispecies

Anti-virals must be selective in their toxicity ie exert their action only on infected cells

Some viruses are able to retain in a latent state e.g herpes, HPV – so drugs that inhibit virus replication aren’t useful here

Some viruses are able to integrate their genetic material into host cells e.g HIV – this integration means you can’t rid the cell of the virus

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6
Q

What virus does Acyclovir target?

A

Targets herpes virus family

Cause common cold sores, muco-cutaneous lesions

Herpes viruses include:

Herpes simplex HSV

Varicella zoster virus VZV

Cytomegalovirus CMV

Epstein-Barr virus EBV

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7
Q

How is acyclovir administered?

What other drugs target herpes virus?

A

Acyclovir

  • IV/Oral/topical
  • For HSV, VZV treatment/prophylaxis
  • CMV /EBV prophylaxis

Ganciclovir

  • IV/oral
  • For CMV

Foscarnet

  • Iv/oral application
  • For CMV

Cidofovir

  • Iv for CMV
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8
Q

What makes acyclovir selective and effective?

A

Only works on virus infected cells

Aciclovir is adminsitered into the infected cell in an inactive form - acyclogluanosine

Inactivated form modified to active form by a viral enzyme, not a cellular enzyme

Viral enzyme, thymidine kinase (TK) activates acyclovir by increasing number of phosphate residues on it

Makes Acyclovir look like a DNA base

Therefore viral DNA pol incoporates only the active form of acyclovir into viral DNA

Acyclovir is very selective for ONLY herpes virus infected cells, making it very effective and safe to use, has low background toxicity

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9
Q

Affinities of enzymes involved in acyclovir

A

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

Acyclovir triphosphatase has 30x the affinity for HSV DNA polymerase compared with cellular DNA polymerase

Acyclovir triphosphatase is a highly polar compound – difficult to leave or enter cells

DNA chain terminator

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10
Q

How does Ganciclovir differ to acyclovir?

A

Active for CMV

  • Reactivated infection or prophylaxis in organ transplant recipients
  • Congenital infection in newborn
  • Retinitis in immunosuppressed

Structurally similar to acyclovir

CMV does not encode TK but has UL97 kinase – has the same functions

Inhibits CMV DNA polymerase

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11
Q

How does foscarnet work?

What is it used for?

A

Anti-herpes virus agents

Selectively inhibits viral DNA/RNA polymerases and RTs

No reactivation required

Binds pyrophosphatase 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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12
Q

What is cidofovir?

What does it treat?

A

Anti-herpes virus agent.

Chain terminator – targets DNA polymerase

Competes with dCTP

Monophosphates 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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13
Q

What are the two mechanisms that cause resistance to anti-virals in herpes viruses?

A

Thymidine kinase mutants

DNA polymerase mutants

If occurs in TK, drugs that don’t need phosphorylation are still active (e.g foscarnet, cidofovir).

If occurs in DNA polymerase, all drugs rendered less effective.

Very rare in immune competent patients (low viral load) - immune system dampens down amount of virus produced by killing infected cells – low amounts of virus, less likely for viral mutants to come that are resistance

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14
Q

What are the structural features of HIV?

A

Double stranded RNA genome

Bound by enzyme, reverse transcriptase, which converts viral RNA to DNA

Two different layers – nucleocapsid protein and matrix capsid which protect viral genome

Lipid membrane

Spike proteins

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15
Q

7 steps in the lifecycle of HIV

A
  1. Attachment with binding of viral gp120 via CD4 and CCRX
  2. Reverse transcription of RNA into dsDNA
  3. Integration of viral DNA into host chromosome
  4. Transcription of viral genes
  5. Translation of viral mRNA into viral proteins
  6. Virus assembly and release by budding
  7. Maturation steps which allow the virus to leave the cell.
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16
Q

What are the four types of anti-HIV drugs?

A
  1. Anti-reverse transcriptase inhibitors
  • Nucleoside/nucleotide RT inhibitors
  • Non-nucleotide RT inhibitors (allosteric)
  1. Protease inhibitors – multiple types
  2. Integrase inhibitors – POL gene – protease, reverse transcriptase and integrase (IN) with the 3’ end encoding for IN (polynucleotidyl transferase)
  3. Fusion inhibitors – gp120/141 - biomimetic lipopeptide
17
Q

How is HIV treated?

A

Highly active anti-retroviral therapy, HAART.

Combination of drugs to avoid resistance.

HIV produces large number of mutations in its replication, easy to generate anti-viral drug resistant mutants. So HAART used.

18
Q

Give example of nucleoside reverse transcriptase (RT) inhibitors

How do they work?

A

AZT-zidovudine

3’-azido-3’deoxythymidime

Look like DNA bases so reverse transcriptase incorporates them into viral RNA and viral DNA

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 – no longer get DNA synthesis

No viral genomes, no viruses, no disease.

Others inhibitors of the same class ddl, ddC, d4T and 3TC (2’,3’-dideoxy-3’-thiacytidine)

19
Q

Example of non-nucleoside reverse transcriptase inhibitors

How do they work?

A

Nevirapine

Same as nucleoside RT inhibitors but don’t look like DNA bases.

Gets incorporated into viral RNA and DNA by RT and terminate production of new viral genomes.

Bind in different ways, can be used synergistically.

Non-competitive inhibitor of HIV-1 RT.

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

20
Q

When is PEP taken?

A

Within 72 hours post exposure to HIV. Taken for 28 days.

2x NRTIs (truvada)

2 tablets 2-24hrs before sex, 1 24hrs after sex, and another 24hrs after - on demand/ event based dosing

the NRTIs can be a combo of nucleoside RTIs

  • emtricitabine (guanosine analog)
  • tenofovir (adenosine analog)
21
Q

What happens when anti-viral resistance occurs?

A

Use of single agents leads to rapid development of resistance

Drug binding site altered in structure by as few as one amino acid substitution

Mutation rate – high

Viral load – high

= more likely a virus carrying a resistance mutation will occur

Selection pressure of presence of drug and mutation frequency

Increased mutation rate seen in HIV

They form a quasispecies within an individual patient – a viral swarm

22
Q

How does amantadine treat influenza virus?

A

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

Now rarely used

23
Q

How does zanamivir and oseltamivir (tamiflu) treat influenza virus?

A

Inhibits virus release from infected cells via inhibition of neuraminidase.

New virus particles being made and trying to leave cell

In order to leave cell there must be interaction with viral protein neuraminidase with cell surface

By blocking this interaction of NA with cell surface, virus no longer released

  • Oseltamivir – oral
  • Zanamivir – inhaled or IV – less likely for resistance to develop
24
Q

Ribvarin is a nucleoside analogue

How does it work?

What does it treat?

A

Block RNA synthesis by inhibiting inosine 5’-monophasphate (IMP) dehydrogenase – this blocks the conversion of IMP to XMP (xanthosine 5’-monophosphate)

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

Ribavirin delivered into infected cell in inactive form

Activated to ribavirin phosphate

Causes chain termination of RNA synthesis

No RNA, no virus, no disease

Easy to get mutations against ribavirin so not used as much

25
Q

What do direct-acting antivirals (DAAs) target in HCV?

What does this targetting allow?

A

Target specific steps in HCV viral life cycle, shortening length of therapy, minimising side effects, targets the virus itself, improve sustained virologic response (SVR) rate.

26
Q

How does HCV infect a cell and what inhibitors can be used to stop it?

A
  1. Entry of virus, release of viral RNA into cytoplasm
  2. Viral RNA produces viral proteins, in order to do this NS3/4 protease is needed
  3. Inhibiting NS3/4 protease inhibits virus replication
  4. Need to make more RNA to make new viruses, inhibiting NS5B polymerase – no more production of viral RNA
  5. Assembly of viral RNA and protein into new viruses, requires the protein NS5A.
  6. NS5A inhibitors = no assembly of viruses, no virus, no disease
27
Q

How is Hep B, Hep C and HIV treated in post-exposure prophylaxis?

A

Hep B

  • Specific Hep B immunoglobulin (passive immunity) + vaccination
  • Within 48 hours (HBV treatment includes antivirals 3TC/NRTIs)

Hep C

  • Interferon-7 and ribavirin (anti-viral) for 6 months within first 2 months of exposure
  • 90% cure rate – now direct acting antivirals

HIV

  • 80% protection i.e no sero-conversion
  • Must be fast – hours
  • Antiviral drug treatment – 28 days
  • 2x NRTI + protease or integrase inhibitor
28
Q
A

Microbiology and immunology (15 decks)

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