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Biotherapeutics > Recombinant Protein Therapeutics > Flashcards

Recombinant Protein Therapeutics Flashcards

1
Q

What are biotherapeutics?

A

Therapies derived from living organisms used to treat chronic diseases

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2
Q

What’s a crucial incentive for innovation into new medicines?

A

Strong intellectual property rights

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3
Q

What is the central tenet of Biotherapeutics?

A

Patient need = disease pathology + treatment agent + MoA + treatment development + treatment manufacture = Performance in Pts

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4
Q

What is diabetes mellitus?

A

Chronic hyperglycemia due to insulin deficiency, resistance or both

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5
Q

What is a late stage complication of DM?

A

Macrovascular disease - CAD, peripheral vascular disease & stroke

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6
Q

What can microvascular damage lead to?

A

Diabetic nephropathy & retinopathy

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7
Q

What is insulin secreted by?

A

Beta cells of pancreatic islets

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8
Q

What is insulin required for?

A

Storage & controlled release of chemical energy available from food

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9
Q

What is insulin’s primary target organ?

A

Liver >50%

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10
Q

What does liver store glucose as?

A

Glycogen
maintains blood glucose at 3.5 - 8.0 mmol/L

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11
Q

What chains make up the insulin monomer?

A

B - 30aa
A -21aa

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12
Q

Why does the monomer have to stay in its specific shape?

A

Has to have this shape in order for it to be recognisable to insulin receptors on hepatocytes

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13
Q

How many aa does the insulin molecule contain?

A

51

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14
Q

When does the insulin molecule assemble into hexamers?

A

In the presence of zinc
Amitosole rings arise from side chains from histadines and circles around sphere of zinc

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15
Q

What is the hexamer?

A

Inactive form with long - term stability - keeps it protected

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16
Q

What is the hexamer-monomer conversion?

A

The central aspects of insulin formulations for injection

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17
Q

Where is prepro insulin cleaved into proinsulin?

A

Golgi

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18
Q

What does proinsulin travel as?

A

Exosomes

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19
Q

How many insulin pathways are there?

A

2

20
Q

What happens when insulin binds to the receptor?

A

hyperphosphorylation of cytoplasmic domains (serine & thyrine) - intermediate signalling proteins activated

21
Q

Is glucose membrane permeable?

A

No

22
Q

How does insulin act in a fasting state?

A

Regulate glucose release by liver

23
Q

How does insulin act in a postprandial state?

A

Facilitates glucose uptake by fat & muscle

24
Q

What is type 1 caused by?

A

Autoantibodies against pancreatic islet proteins

25
Q

What is Type 2 caused by?

A

Age
obesity
ethnicity
family history

26
Q

What diseases are type 2 associated with?

A

Obesity
hypertension
decreased HDL
hypertriglycerideameia
insulin resistance

27
Q

What are 3 therapeutic modalities for T2DM?

A

Incretins
short acting insulin
long acting insulin

28
Q

What is the MoA of short acting?

A

Pre-meal injection (sub cutaneous)
absorbed slowly (peak at 60-90 mins after)
May last too long leading to hypoglycaemia

29
Q

What are 3 sort acting insulins?

A

Insulin lispro
insulin aspart
insulin glulisine

30
Q

What is the change in insulin aspart?

A

Switched proline for an aspartic acid (-vely charged)
poor hexamer structure = rapid dissociation

31
Q

What is the change in insulin lispro?

A

Switched position of 2 aa - instability created

32
Q

What is insulin structure modified to in long lasting?

A

Delay absorption to prolong duration of action eg. insulin glargine

33
Q

What is insulin glargine soluble as?

A

In a vial at pH 4 but precipitates when SC injected

34
Q

How is insulin glargine engineered?

A

Replace Asp at 21 of A chain with glycine & adds 2 asparg. to end of B chain

35
Q

What does insulin detemir have?

A

fatty acid tail - binds to serum albumin - slow dissociation kinetics from bound state - prolonged action

36
Q

What can lysine form?

A

Lysine has an amino side chain - can form an ionic bond with another moiety - as long as there is no other lysines in the chain

37
Q

What is combination therapy?

A

Multiple injection regiment with short acting insulin
longer lasting at night

38
Q

What has Oramed POD technology been designed to?

A

Protect orally delivered proteins from unwanted enzymatic activity within GIT
Enhance absorption across intestinal wall

39
Q

What are incretins?

A

Insulin response due to release of 2 peptide hormones from L cells in the intestine

40
Q

What are 2 types of incretins?

A

GLP-1
Glucose dependent insulinotropic peptide

41
Q

What are 2 peptide analogues of GLP-1?

A

Exenatide
Liguratide

42
Q

What is the Moa of exenatide?

A

Promotes insulin release & inhibits glucagon - reduce appetite & gastric emptying & slows postprandial increase in glucose

43
Q

How long is glucagon?

A

180aa
~21kDA

44
Q

What is semaglutide?

A

Potent, long-acting GLP-1 administered SC once weekly
94% homology with native GLP-1

45
Q

What are 3 structuraly changes in semaglutide?

A
  1. substitution of Ala with Ab at position 8 increases enzymatic stability (protects from DPP-4 degradation)
  2. attachment of linker & C18 dl-acid at position 26 ( strong albumin binding)
  3. substitution of Lys with Arg at position 34 prevents C18 fatty acid binding at wrong site
46
Q

What is GLP-1 RAs to be the 1st line therapy for?

A

CV risk reduction in patients with T2DM with very high/high risk

47
Q

Which insulin strains were produced in e.coli?

A

Humulin
exubera
isulin lispro
insulin glusine
insulin glargin

Biotherapeutics (3 decks)

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