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Drug Disco > AW NEUR > Flashcards

AW NEUR Flashcards

0
Q

HA receptor?

A

Sialic acid

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1
Q

Function of heamagluinin?

A

Attachment and penetration of virus onto cells

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2
Q

neuraminidase function

A

Cleaves Sialic acid from glucoconjugates

Release of progeny virons from infected cells

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3
Q

M2 viral surface protein has functions in ….

A

Uncoating and maturation

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4
Q

Two sections of the HA structure…

A

Globular head and fibrous stem

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5
Q

What happens to HA in internalisation?

A

Shape change

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6
Q

How does m2 work?

A

Pumps protons into the virus when into in the host - uncoating

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7
Q

What happens in budding

A

Viral particals bud and remain attached via Sialic acid-HA Neuraminidase cleaves this

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8
Q

Current NA inhibitors?

A

Relenza (zanamivir)

Oseltamivir (Tamiflu)

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9
Q

NA are …. Inhibitors, active against….

A

Competative, active against all strains of influenza

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10
Q

NA inhibitor design started through…3

A

Random screening
Later mechanism based design
Later structure based design

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11
Q

What can we do to make the substraight bind tighter…?

A

Make it look like the transition state (FANA 10000 times more potent)

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12
Q

Design of relenza was via …

A

Rational drug design using x-ray crystal structure

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13
Q

Introduce Pharmacophores (into relenza) to improve 2+4

A

Mainly - Specificity/selectivity - Toxicity
But also
- Specific activity (ie. potency, IC50, Ki)
- Bioavailability (logP)
- Half-life
- Route of administration

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14
Q

Why did we worry about tox?

A

Humans have their own NA essential to function

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15
Q

why is there an ionic bond in relenza?

A

There was a space in that visualised section of binding,

There was an h bond but an ionic bond is much stronger so replaced it.

16
Q

Why is there guanidine group on relenza?

A

Used crystal structure to show
Big basic group to from ionic bond and
Extra h bonds formed

17
Q

How is relenza administered ?

A

Inhalation… The focus in production was all on selectivity.

18
Q

Age of relenza?

A

7 plus

19
Q

Does relenza work?

A

Must be administered < 48 hours after onset of illness
• Reduce symptoms and decrease length of illness due to influenza A & B virus infections by approximately 1 day
• Decrease viral shedding

20
Q

Advantage and disadvantage of the rotadisk relenza admin?

A

Minimal resistance has been observed

However dry powder is not really practical for resp infection.

21
Q

BA of relenza…
Serum half life
Route of excretion

A

• Bioavailability of zanamivir delivered by inhalation is ~10 to 20%
• Serum half-life is 2.5 to 5 hours
• Zanamivir is excreted unchanged by the kidney
• But dose adjustments are not necessary in renal insufficiency

22
Q

FANAs IC50 is improved a lot by

A

The guanadino group (form relenza)

23
Q

Tamiflu, why remove the glycerol side chain and replace with hydrocarbons.,

A

Improve lipophilicity

Improve complementarity to protein

24
Q

Tamiflu: Why remove the o from the ring?

A

Increase stability

25
Q

Tamiflu improvements were based around trying to…

A

Increase oral BA

26
Q

Tamiflu …. Et instead of ionic group becuase

A

Lopophilic, improve oral BA

27
Q

Tamiflu pentanyl ether… How did that happen

A

Was introduced completely by accident, x ray crystal structure suggested it wouldn’t work as too big to fit enzyme

28
Q

Why is the pentanyl ether good?

A

Makes it completely selective to viruses, creates large lipophilic pocket , human cannot do this conformational change

29
Q

Double bond in ring of Tamiflu is for..

A

Mimic transitional state

30
Q

Admin and treatment of Tamiflu

A

75 mg tablets and syrup for children • Approved for treatment and prophylaxis of influenza A and B • Treatment ≥ 1 year • Chemoprophylaxis ≥ 13 years

31
Q

BA of Tamiflu

A

80%

32
Q

Half life and metabolism of Tamiflu

A

Active drug has a serum half-life of 8-10 hours, and is excreted unchanged by the kidney Frequency of oseltamivir dosing may be reduced when creatinine clearance < 30 ml/min

33
Q

Adverse effects of Tamiflu

A

15% nausea and vomiting , reduce if taken with food
Only 1-2% stop because of adverse events Headache reported in older adults Cases of hypersensitivity reactions, rash, hepatotoxicity, and thrombocytopenia reported rarely

34
Q

Levels of resistance to Tamiflu…

A

18% possibly higher

35
Q

How does resistant to Tamiflu happen

A

Histamine residue mutates to become tyrosine. , this is a lot bigger and fills up the space we need for binding

36
Q

Conclusions from Tamiflu resistance

A

Make the substrate as much like the endogenous prod it’s as possible to avoid resistance
Minimalist theory of drug design

37
Q

Why has Tamiflu made so much more money than relenza

A

Into all in mode of administration because in every other way it’s a worse drug

Drug Disco (12 decks)

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