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Pharmacology (MPAS) > Lecture 20: antiviral drugs > Flashcards

Lecture 20: antiviral drugs Flashcards

1
Q

What are some characteristics of viruses?

A

Obligate intracellular parasites

No cell wall or plasma membrane

No metabolism (tough to target)

Few drugs block reproduction selectively

Pharmacology focused on late symptoms

Few virus groups can be effectively treated with drugs

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2
Q

Virus classification

A

(+)ssRNA - HIV, Hep A and C (can give direct protein synthesis)

dsDNA - Hep B, Herpes

(-) ssRNA -Influenza

See figure

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3
Q

What are the cytopathic effects of viruses?

A

Host cell metabolism hijacked

Viral-induced suppression of host homeostasis

Viral proteins induce lysis or apoptosis

Viral proteins trigger host immune response

Inflammatory reaction kills host

All above involve lytic cycle (generation of new virus)

Viruses can become latent, host cell survives

No overt immune response

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4
Q

What cells does Herpes simplex virus target?

A

Neurons (neurotropic)

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5
Q

What type of genome does HSV have?

A

Complex dsDNA

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6
Q

What symptoms does HSV cause?

A

HSV-1: cold sores

HSV-2: genital herpes

Chicken pox (varicella zoster - VZV), shingles, cytomegalovirus

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7
Q

How is HSV transmitted?

A

Close contact

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8
Q

HSV life cycle

A

Lytic cycle: in epithelial cells (80 genes in cascade)

Viral progeny spread to sensory neurons

Virus is retrogradedly transported to the cell body of the neuron

Latent infection: circular episomal DNA (not incorporated into genome)

No immune signature, no cytotoxic effect

Stress-related reactivation

Anterograde transport (similar to how neurotransmitter is transported)

See figure

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9
Q

HSV replication

A

Viral DNA enters nucleus and circularizes

Immediate early genes (IEG) are transcripts by the host RNA polymerase (2-4 hours post infection).

This transcription uses host transcription factors and VP16, a viral activator protein, which binds host cell factor that activates OCT1 (host transcription factor)

IEG proteins trigger early genes

E proteins control viral DNA replication

DNA replication initiates late genes, which are responsible for viral structure and assembly

See figure

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10
Q

How does acyclovir work?

A

HSV treatment

The viral thymidine kinase converts acyclovir to acyclo-GMP.

Host enzymes convert acyclo-GMP to acyclo-GTP.

Acyclo-GTP is incorporated into the growing DNA, and causes chain termination.

It is an inhibitor of the viral DNA polymerase.

See figure

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11
Q

Where is cytomegalovirus (CMV) a problem?

A

In immuno-compromised patients (organ transplantation)

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12
Q

What are the complications of CMV?

A

Liver failure

Colitis

Retinitis (inflammation of retina, can cause blindness)

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13
Q

What type of virus is HIV?

A

Lentivirus (HIV-1 and HIV-2)

Retrovirus family (+) ssRNA virus

Fast replication cycle and multiple infection

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14
Q

What enzymes is most responsible for drug resistance in HIV?

A

Reverse transcriptase

Enzyme is error prone = drug resistance

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15
Q

What does HIV cause?

A

AIDS

90% of people progress to AIDS within 10-15 years

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16
Q

How is HIV transmitted?

A

Blood/fluid

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17
Q

What cells does HIV invade?

A

T helper cells (CD4+)

Macrophages, dendritic cells

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18
Q

What receptors does HIV target?

A

CD4 receptors and chemokine co-receptors (CCR5, CCR4)

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19
Q

What types of immunity are lost in HIV infection?

A

Cell-mediated immunity

Loss of CD4+ cells

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20
Q

Development of aids - CD4+ count and HIV RNA copies

A

See figure

Initially, during primary infection, the CD4+ cell count is high. The virus starts to replicate rapidly, which causes the CD4+ cell count to drop

During clinical latency, the virus replicates slowly, and the CD4+ cell count drops

Eventually, there are very low CD4+ cells in the blood, and the virus takes over

This predisposes the host to opportunistic diseases etc.

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21
Q

Epidemiology of HIV

A

High in Africa

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22
Q

Origin of HIV

A

Started in Africa

Person from Haiti travelled to Africa and likely contracted HIV from a sex worker

Haitian then returned to haiti and transmitted virus by donating blood

People visiting Haiti for vacation contract the virus

See figure

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23
Q

Treatment options for HIV

A

No cure

Post-exposure prophylaxis

Highly active antiretroviral therapy (HAART) - 3 drugs belonging to at least 2 classes

Newer integrase and entry inhibitors can be added

Aggressive treatment in children

24
Q

Points of intervention in HIV replication cycle

A

See figure

Fusion inhibitors

CCR5 antagonists

Reverse transcriptase inhibitors

Integrase inhibitors

Protease inhibitors

25
Q

NRTI mechanism of action

A

Nucleoside/nucleotide reverse transcriptase inhibitors

Analog of native ribosides, but lack 3’ hydroxyl.

Phosphorylated to triphosphate by host enzymes. Incorporated into viral DNA.

Lack of 3’ hydroxyl leads to DNA chain termination.

26
Q

How do NRTI’s affect mitochondria?

A

Each mitochondria has it’s own DNA

The normal process of energy production produces free radicals

Free radicals can act on mt DNA and damage it

Mitochondria get around this by producing new mitochondria

However, AZT inhibitors the DNA polymerase in mitochondria, so they get destroyed and cannot regenerate

Cell death

27
Q

Which NRTI is recommended in pregnant women?

A

Lamivudine

28
Q

Which NRTIs have long half lives?

A

Emtricitabine (39 hours)

Tenofovir

29
Q

Mechanism of NNRTIs

A

Non-competitive inhibitors of HIV-1 reverse transcriptase

No activation required

No effect on bone marrow or mitochondrial DNA polymerase

30
Q

Mechanism of HIV protease inhibitors

A

Reversible inhibitors of HIV aspartyl protease

Prevents proteolysis of viral polyprotein = virus does not get released

Prevents maturation of viral particles

Non infectious virus produced

31
Q

Mechanism of action of HIV integrate inhibitors

A

Normally: integrase binds to viral DNA and catalytically processes 3’ ends. Integrase then joins viral and cellular DNA.

Integrase inhibitors block strand transfer into the host DNA

See figure

32
Q

Mechanism of co-receptor and fusion inhibitors

A

See figure

33
Q

What HIV protein mediates cell fusion?

A

gp41

36 amino acid

34
Q

What are the most common influenza viruses?

A

Flu A and Flu B

35
Q

What carries flu A?

A

Aquatic birds (domestic birds)

36
Q

Which flu is the most severe

A

Flu A

Spanish flu pandemic 1918-1919

40-100 million died

37
Q

How does resistance against influenza drugs arise?

A

No RNA proof reading in the flu virus

38
Q

What type of genome does the influenza virus have?

A

(-)ssRNA

39
Q

How is influenza transmitted?

A

Aerosol passage

40
Q

What cells does influenza attack?

A

Epithelial cells

41
Q

What are the key proteins of influenza virus? functions?

A

Hemagglutin (Hag) - binds to sialic sugars on host cells

Neuraminidase cleaves sialic residues to release virus

M2 ion channel - proton channel that modulates pH (uncoating)

See figure

42
Q

What is the influenza virus life cycle?

A

Hag binds to cell surface

Mediates endocytosis of particle

M2 regulates uncoating

M2 controls Hag processing

Release of particles from buds requires neuraminidase

See figure

43
Q

Mechanism of neuraminidase inhibitor - influenza

A

Viral neuraminidase: glycoside hydrolase enzyme

Cleaves glycosidic linkages on neuraminic (sialic) acid

Permits release of viral particle from host cell

Neuraminidase inhibitors block this

44
Q

Mechanism of action of inhibitors of viral uncoating - influenza

A

Block M2 channel. Prevents acidification of viral particle. Stop releasing of viral genome and uncoating

45
Q

What type of genome does hepatitis B have?

A

dsDNA

But uses RT

See figure

46
Q

How are hepatitis B and C transferred?

A

B: Blood-blood, 2 billion people infected

C: blood-blood, 200 million infected

47
Q

What is the most common form of hepatitis virus?

A

B

48
Q

Is vaccination against hepatitis B possible?

A

yes

49
Q

What occurs in persistent Hep B infection?

A

cccDNA

covalently closed circular DNA (circular DNA that exists outside the genome)

50
Q

Type of genome in hepatitis C virus?

A

(+)ssRNA

51
Q

Symptom detection in hepatitis C

A

Difficult to detect

52
Q

When is interferon treatment used in Hepatitis infection?

A

Chronic infection only

53
Q

Mechanism of interferon treatment in hepatitis

A

Raises cell resistance in liver

Cells are in an “antiviral state”

Elevates MHC1 - presentation to cytotoxic CD8 T cells (enhanced cell mediated immunity)

Increase p53 - apoptosis

54
Q

How does innate induction of interferon occur?

A

By high levels of dsRNA or foreign RNA

55
Q

What is standard therapy for HCV?

A

Ribavirin plus peg interferon alfa

56
Q

Which viruses use reverse transcriptase?

A

HIV and HBV

57
Q

Anti HBV drugs

A

NRTIs = DNA chain termination

Lamivudine, tenofovir

Combined with interferon

Pharmacology (MPAS) (19 decks)

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