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Virology > Exam III: Lecture 9 > Flashcards

Exam III: Lecture 9 Flashcards

1
Q

Why is it hard to find a drug that is solely active against a virus and not against the host?

A

Viruses use a ton of host machinery and the mutation rate is high

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2
Q

What is an example of an antiviral target found in viruses but not in host cells?

A

RDRP

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3
Q

What are the 6 classes of antiviral drugs?

A
  1. Chemotherapy
  2. Nucleoside analogues
  3. Necleotide analogues
  4. Non-nucleoside reverse transciptase inhibitors
  5. Protease inhibitors
  6. Antiviral proteins
  7. Other
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4
Q

How do nucleoside analogues function? What prerequisite step is required?

A

Bind and inhibit enzymes involved in replication = freezes the cell
They need to be metabolized into their active form by phosphorylation

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5
Q

How do nucleotide analogues function?

A

Freezes the cell
They have a phosphate group attached to them and persist in the cell for a long time
??

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6
Q

What is an example of an antiviral protein?

A

IFNalpha for Hep C

The first defense against an RNA virus

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7
Q

4 ways to block viral attachment?

A
  1. Antireceptor antibody = antibodies block receptor
  2. Soluble form of the receptor = virus binds to free-floating receptor instead of cell
  3. Capsid binding = block attachment of the capsid protein to the receptor
  4. Receptor Ligand = flood with normal ligand and the virus has no where to bind because the receptors are full
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8
Q

What is the problem with antibody treatment?

A

It is very expensive and the patient would need to be hospitalized

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9
Q

Why is penetration/uncoating hard to inhibit?

A
  1. The drug etc must get inside the cell

2. Symptoms dont start until penetration/uncoating has already taken place

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10
Q

What is an example of a penetration/uncoating inhibitor? (General and specific)

A

Inhibitor of ion channels > prevents acidification of the endosome
Amatadine = M2 inhibitor (proton channel on influenza virus)

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11
Q

What is Amatadine? What step does it inhibit?

A 
M2 inhibitor (M2 = proton channel)
Blocks uncoating by preventing the acidification of the endosome
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12
Q

Is targeting genome replication easy or hard? Why?

A

Relatively easy since many viruses have their own replication machinery

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13
Q

Drugs that target genome replication have short or long half lives in the blood?

A

Short

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14
Q

What is Acyclovir? What step of the lifecycle does it inhibit? What classification of antiviral does it fall under? Mechanism of action?

A

Genome Replication
Nucleoside analogue
Enter cell in inactive form > triphosphorylated > enters viral genome > viral polymerase things it a nucleotide > embedded into viral genome > replication halts once it reaches acyclovir because it lacks the required sugar

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15
Q

Does acyclovir work against active or latent viruses?

A

Active = they must be performing translation in order for acyclovir to work

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16
Q

What makes acyclovir virus-specific? What virus does it treat?

A

Acyclovir requires herpes kinase to do the 1st phosphorylation = HSV Thymidine Kinase

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17
Q

Why is assembly/maturation/release not a very desirable part of the virus life cycle to inhibit?

A

The damage is already done

Plus there are 1000s of virus particles in cell and that would be a lot of target

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18
Q

What is Tamiflu? What step of the lifecycle does it inhibit? What virus does it treat? What is its mechanism of action?

A

Prevents egress
Influenza
Neuraminidase inhibitor = blocks the necessary cleavage of the sialic acid influenza is attached to

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19
Q

What is the chemotherapeutic index?

A

(dose of the drug which inhibits virus replication) / (does of drug toxic to the host )

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20
Q

Do you want a high or low chemotherapeutic index?

A

Low

Low dose to be effective / high dose needed for toxicity

21
Q

How does ‘magic bullet’ tie into the chemotherapeutic index?

A

The idea of a magic bullet is that a substance can specifically target disease-causing organisms in the body without causing harm to the rest of the body

22
Q

Who is Paul Erlich?

A

Won the Nobel prize
“Magic Bullet”
Drug against syphilis = neosalvarsan = 1st magic bullet

23
Q

What are the 2 ways a drug gets developed?

A
  1. Discovery by ‘accident’

2. Discovery by ‘design’

24
Q

Tell me about discovery by ‘accident’ (2)

A
  1. Previously identified compounds that were used for the treatment of other diseases are now being used as antivirals
  2. Chemical compounds are created using simple organic reactions > test 1000 compounds
25
Q

What is high throughput screening? what are the 2 methods?

A

All done by a robot > can lead to the identification of compounds that are further modified for efficacy

  1. Cell based: against infected cells
  2. Target based: against viral proteins
26
Q

Tell me about the 2 general steps of drug discovery by ‘design’

A
  1. Start with a product that is an enzyme, substate, or other viral molecule
  2. Create a compound that either inhibits/mimics/etc the staring product
    You’re working backwards
27
Q

Drugs must target a process that is essential for viral replication. Why?

A

They are almost always used AFTER infection

28
Q

Talk me through the rational drug design against picornavirus?

A

Picornavirus has a specific capsid protein (VP1) which binds to a host cell receptor
VP1 has a canyon that the receptor must fit perfectly
Design a compound to sit inside the canyon = inhibit attachement

29
Q

In the field of observation, chance favors only the prepared mind. What was the story that went along with this?

A

Serendipity
Fleming noticed that one of his bacterial plates had started growing a fungus, but where the fungus was the bacteria did not grow = the fungus was producing penecillium

30
Q

What are direct-acting antivirals? How are they selected? What is the advantage of direct-acting antivirals?

A

Antivirals targeted against specific proteins encoded by the virus
Selected by high throughput screening OR designed toat way
Fewer side effects / more potent to the virus

31
Q

Talk me through the drug design of an NS3 protease inhibitor for Hep C? (general)

A

Enzymes are easy targets to inhibit because they have an active site which is essential for function

  1. Create a computer model for NS3 = determine specific substrate + enzyme interactions
  2. Determine the minimal requirements for substrate recognition (ie how many aa does the enzyme actually bind to)
  3. Create a molecule that mimics the substrate = competitive inhibitor (potenitally change side groups to make your substrate bind with higher affinity than the viral protein)
  4. Test its effectivity
32
Q

What are the 5 specific steps used to create NS3 protease inhibitor?

A
  1. Determine minimal requirements for substrate recognition
  2. Use a minimal substrate peptide to determine the requirements for recognition
  3. Use fragments of the N-terminal obtained after cleavage as a competitive inhibitor
  4. use a weak hexapeptide as a starting point to create a more potent inhibitor
  5. Narrow this down to a tripeptide mimetic and test inhibitor activity
33
Q

What is BILN 2061? What virus does it treat?

A

Macrocyclic inhibitor of NS3 protease
Binds better to NS3 protease than viral substrate
HCV genotypes 1a and 1b

34
Q

What tests can be performed to test inhibitor specificity? (6)

A
  1. Protease Assay
  2. Surrogate cell-based assays
    2a. Toxicity assay
  3. Secondary Activity
  4. Western blot
  5. Pharmacokinetic study
  6. Clinical Trial: Infected Patients
35
Q

What does a protease assay measure? What value does it give you? How do you tell it if is “good”?

A

Measures how well the substrate inhibits the pure enzyme
Gives you Ki value
Compare the Ki values of the normal substrate and the substrate you made, the higher the Ki the better ?

36
Q

What does a surrogate cell-based assay tell you? What value does it give you? How do you tell if it is “good”?

A

Tell you the amount of drug needed to inhibit viral replication (how much of your substrate do you need)
EC50 - how much drug it takes to inhibit the replication by 50%
The lower the better

37
Q

What does a cytotoxicity MTT assay measure? What value does it give you? How do you tell if it is “good”?

A

The concentration at which the “drug” would kill half the cells
CC50
The higher the better

38
Q

What does a secondary activity assay measure? What value does it give you? How do you tell if it is “good”?

A

Measures at what concentration it will effect human enzymes
IC50
The lower the better

39
Q

What does a western blot measure? How do you tell if it is “good”?

A

Tests the mechanism of inhibition
If it works by cleavage you should see two bands or the lack of two bands
You can also test different concentrations to see the most effective

40
Q

What does a pharmacokinetic study measure? How do you tell if it is “good”?

A

How long a drug persists in the body
Complete cytochrome complex in liver
Just need to find the concentration that lasts for the desired duration

41
Q

What does a clinical trial with infected patients measure? How do you tell if it is “good”?

A

Measure viral RNA with PCR to determine viral load
You want to see a drop in viral load after the first dose and a climb in viral load after stopping treatment = proves the drug caused the drop

42
Q

What is Ribavirin? What virus does it treat? Mechanism? Target?

A

Broad spectrum, HSV, measles, Lassa
Triazole carboxamide
RNA mutagen

43
Q

What is Amatadine? What virus does it treat? Mechanism? Target?

A

Treats Influenza A
Tricyclic amine
Matrix protein, HA

44
Q

Nevirapine; virus, mechanism, target

A

Retroviruses
Necleoside Analogue
RT

45
Q

Indinavir; virus, mechanism, target

A

HIV
peptide analogue
HIV protease

46
Q

What is the advantage of getting infected with viruses?

A

If infection occurs during childhood (esp for Chicken pox, measels) it can make the patient immune to infection during adulthood when the infections can be more serious

47
Q

What are 6 ‘antivirals’ guaranteed to work?

A
  1. Wash your hands frequently with soap
  2. Avoid contact with the saliva of other people
  3. Protect yourself during sex
  4. Limit the number of partners
  5. Avoid needle sharing
  6. Eat and drink cooked and boiled food
48
Q

What is an example of a beneficial virus?

A

Pegivirus can reduce infection by HIV

49
Q

What observation was KEY to Jenner’s development of the smallpox vaccine?

A

???

Virology (22 decks)

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