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LF213: Virology > Lecture 10. Antiviral Therapy > Flashcards

Lecture 10. Antiviral Therapy Flashcards

1
Q

What are viruses insensitive to?

A

Antibiotics

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2
Q

What do antivirals need to be when compared with antibiotics?

A

Much more specific (no broad spectrum drugs)

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3
Q

What types of infections do most antivirals target?

A

Chronic, persistent or latent viral infections (e.g HIV, herpesviruses and hepatitis C due to the window of opportunity to treat them)

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4
Q

What else is important for success in viral infections?

A

An intact immune system is important for success in treating viral infections
Antivirals don’t tend to destroy viral particles, just inhibit them

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5
Q

What are the properties that antivirals need to have?

A

Specificity and potency in vitro
Good selective index
Good therapeutic index
Good oral bioavailability if possible

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6
Q

What does it means for a drug to have good specificity and potency in vitro?

A

Specificity = drug needs to be specific at inhibiting enzyme or virus without being toxic to own cells
Potency = how effective it is at clearing/inhibiting viral replication

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7
Q

What is an example of what we mean by specificity and potency in vitro?

A

Compound X inhibits viral enzyme Y at a concentration of 100 nM in vitro. At this concentration, compound X does not affect cells

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8
Q

What does a good selective index mean?

A

Calculating 50% toxic concentration/50% virus inhibitory concentration (in vitro)

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9
Q

What is an example of what we mean by good selective index mean?

A

Compound X is toxic to cells at a concentration of 5 mM, but it inhibits the growth of virus in cells by 50% at a concentration of 200 nM
Selective index = 5x10⁻³/2x10⁻⁷ = 2.5x10⁴ / 25000
Range of x10³ - x10⁶ what we’re aiming for

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10
Q

What does a good therapeutic index mean?

A

Minimum toxic dose/therapeutic dose (in vivo)

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11
Q

What is an example of what we mean by good therapeutic index mean?

A

Compound X is toxic to mice at 10 mM but clears virus from the mice at 20μM
Therapeutic index = 1x10⁻²/2x10⁻⁵ = 5x10³ (5000)

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12
Q

Why is the therapeutic index different to the selective index?

A

Selective index is measured in vitro whilst the therapeutic index is measured in vivo

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13
Q

What is pharmacokinetics?

A

The variation in the circulating blood concentration of a drug under a particular dose regime

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14
Q

What is pharmacokinetics influenced by?

A

Absorption - how well does the drug get into circulation?
Distribution - does it get into the right tissues?
Metabolism - how quickly is it broken down in the body? (also depends on how drug is taken)
Excretion - how quickly is it excreted from the body?

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15
Q

What is bioavailability?

A

The fraction of administered drug that makes it into the circulating bloodstream

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16
Q

What does good oral bioavailability mean?

A

If you take something by mouth (e.g tablet), how much will end up in the bloodstream
Also increases drug compliance

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17
Q

What properties influence oral bioavailability?

A

Properties such as acid stability and resistance to digestive enzymes required

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18
Q

What two ways can new antiviral compounds be discoevered?

A

Directly or random

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19
Q

What is the random way that new antiviral compounds can be discovered?

A

High throughput screening of small molecules for virus growth inhibition in cell culture or for enzyme inhibition in vitro (worth noting not all viruses grown in cell culture or can be purified for assay)

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20
Q

What is the directed way that new antiviral compounds can be discovered?

A

Molecular modelling - using known 3D structures of proteins, substrates, interactions to design inhibitors to make antivirals that inhibit active sites etc.

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21
Q

What is structure-activity relationship testing?

A

When you make modifications to enhance the activity or pharmacokinetics of lead compounds (multiple rounds of this)
Starts relatively random in vitro until moving on to work in animals to see effects and enhance pharmacokinetics

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22
Q

What do in vitro studies of antiviral effect and cytotoxicity provide?

A

Good selective index

23
Q

What do animal models for safety and activity provide?

A

Good therapeutic index

24
Q

How many phases of clinical trials in humans are there, how often do they last, and how much do they cost?

A

4 phases (phases I to IV)
Normally takes 10 years
Costs £400M

25
Q

What happens in Phase I of clinical trials (also known as first-in-man trials)?

A

Small number (10-50) of healthy volunteers
Single small dose increasing to higher multiple doses
Monitor for adverse effects and pharmacokinetics (40% fail phase I)

26
Q

Why do ~40% of antivirals fail Phase I?

A

Not usually because of safety, but pharmacokinetics (all excreted for example)

27
Q

What is a Phase 0 clinical trial?

A

Only used by some companies, looks at the bioavailability of the antiviral

28
Q

What happens in Phase II of clinical trials?

A

Small number (50-100) of patients (not healthy volunteers)
IIa - confirm metabolism is same as healthy volunteers
IIb - compare with placebo for efficacy. Usually double-blinded (these days, standard treatments are more commonly compared with new antiviral instead of placebos)
Another 30% of drugs fail phase II (again normally due to efficacy instead of health reasons)

29
Q

What happens in Phase III of clinical trials?

A

Large numbers (1000s) of patients
Randomised double-blind trial versus placebo and existing treatments
Much larger numbers so you an get a better statistical power with the efficacy - pick up on problems that don’t appear with smaller sample sizes (interactions with other diseases and/or drugs)

30
Q

What happens in Phase IV of clinical trials?

A

After approval for marketing
Large scale, broader patient population
Monitored for long term effectiveness and long term side effects (side effects that have appeared years after treatment)
Further studies may test the drug in new age groups or patient types, and in new formulations

31
Q

What are examples of antivirals used against HIV?

A

Nucleoside reverse transcriptase inhibitors
Non-nucleoside reverse transcriptase inhibitors
Protease inhibitors
Integrase inhibitors
Fusion inhibitors
Resistance and combination therapy

32
Q

What are the targets for anti-HIV therapy?

A

The viral enzymes or the viral processess

33
Q

What viral enzymes are targeted by anti-HIV therapy?

A

Reverse transcriptase - makes dsDNA copy of HIV RNA genome
Protease - cleaves Gag and Gag/Pol polyproteins into structural and enzymatic viral components
Integrase - catalyses insertion of dsDNA copy of viral genome into host cell chromosome

34
Q

What viral processes are targeted by anti-HIV therapy?

A

Cell attachment and entry - HIV envelope proteins bind to cell surface receptors and cause membrane fusion

35
Q

What are nucleoside reverse transcriptase inhibitors (NRTIs)?

A

Phosphorylated by cellular enzymes to the triphosphate form
Bind the active site of RT preferentially, incorporated into viral DNA causing chain termination

36
Q

What was the first anti-HIV drug?

A

Zidovudine (AZT) my beloved
Thymidine analogue
Incorporated into DNA instead of TTP

37
Q

What are examples of current NRTI frontline drugs?

A

Lamivudine (cytidine analogue)
Emtricitabine (cytidine analogue)
Abacavir (guanidine analogue)
Tenofovir (adenosine analogue)

38
Q

What are non-nucleoside reverse transcriptase inhibitors (NNRTIs)?

A

Diverse chemical structures. Bind to an allosteric site on RT (known as the NNRTI pocket)
Changes the conformation of the reverse transcriptase so it cannot catalyse reactions
Very specific – active against HIV-1 but not HIV-2

39
Q

What was the first NNRTI and what is the current frontline NNRTI used?

A

First: Nevirapine
Frontline: Efavirenz

40
Q

What are protease inhibitors?

A

Antivirals that cleave the protease cleavage site of HIV, cutting between the Phe and Pro in the following sequence
Leu-Asn-Phe-Pro-Ile

41
Q

What was the first protease inhibitor and how did it function?

A

Saquinavir - 1995
Transition state analogue of the proteolytic cleavage reaction
Has some of the same amino acids that bind into the active site, blocks substrate from getting into the active site

42
Q

What are examples of current frontline protease inhibitors?

A

Indinavir
Atazanavir
Fosamprenavir

43
Q

What are integrase inhibitors?

A

Inhibits strand transfer between the viral DNA ends and cellular DNA

44
Q

What was the first integrase inhibitor and when was it approved?

A

Raltegravir - approved Oct 2007

45
Q

What was the first fusion/cell entry inhibitor?

A

First entry inhibitor was enfuvirtide (T20)
Prevents hairpin formation so HIV and host cell membranes not brought together for fusion
36 amino acid peptide that binds HIV envelope protein (gp41) and prevents the conformational change required for fusion

46
Q

When are fusion/cell entry inhibitors approved for patients?

A

Approved for patients in whom other drugs have failed

47
Q

What are the downsides of using fusion/cell entry inhibitors?

A

Very expensive; difficult regimen (self-injection); 98% skin reactions

48
Q

What do the next generation of entry inhibitors target?

A

Target cell surface receptors used by HIV for entry:
Maraviroc (Aug 2007) - blocks CCR5
Ibalizumab (March 2018) - monoclonal antibody against CD4 and also non-immunosuppressive; successful against multi-drug resistant HIV

49
Q

How does antiviral resistance form?

A

All current HIV drugs select resistant mutants. These mutant viruses then grow to dominate the population
Resistance is due to amino acid substitutions in the viral protein target of the drug.
Protease and integrase mutants arise less rapidly than reverse transcriptase mutants

50
Q

In which groups of antivirals is cross-resistance seen in particular?

A

NNRTIs
Any mutations that occur allow the virus to become resistant to anti-viral drug, rapid spread in the population until mutation becomes dominant

51
Q

What is the standard therapy for HIV?

A

Combination therapy:
Virus replication is suppressed to a minimum, less chances to mutate
Virus takes much longer to develop resistance to 3 different drugs
Any resistant viruses that do evolve are likely to be less virulent
Can target multiple cell types and mechanisms of distribution
Combination makes it harder for virus to mutate/spread

52
Q

What is the current treatment regime for HIV?

A

Highly Active Antiretroviral Therapy (HAART):
2 NRTIs + 1 NNRTI or 2 NRTIs + 1 PI (protease inhibitor)

53
Q

What can some triple combination treatments come in now?

A

The same pill eg. Atripla (200 mg emtricitabine, 300 mg tenofovir, 600 mg efavirenz)
Increases adherence to treatment regime – less likely to develop resistance

LF213: Virology (14 decks)

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