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Drug Disco > Aw Biologicals > Flashcards

Aw Biologicals Flashcards

0
Q

Biologicals are isolated from 3 sources…

A

Humans
Microorganism
Animal

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1
Q

Three eg of biologicals

A

Vaccines
Recombinant proteins and peptides
Gene therapy

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2
Q

Why are bio at the front of the market.

A

They’ve already evolved to rurally bind to a particular target which is an advantage

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3
Q

May be used to treat conductions where there is nothing else available:

A

-oncology -rheumatology -cardiology

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4
Q

In 2006 the bio market was % of sales and worth…

A

10% and worth £35 bn

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5
Q

Earliest example of a biological

A

Insulin

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6
Q

Fuzeon

A

Aniti HIV fuzeon inhibitor

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7
Q

Fuzeon works by

A

Blocking entry of HIV into CD4 or T cells

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8
Q

Fuzeon mimics

A

GP41 on the surface of the virus, parenting normal fusion.

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9
Q

Why can we used fuzeon with other theroapies?

A

Targets alternative mechanism

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10
Q

Fuzeon is composed of ….. And is produced…

A

36 amino acids, produced synthetically

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11
Q

HIV membrane contains trimeric glycoprotein spikes containing …

A

gp41 and gp120 subunits

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12
Q

Fusion begins with ….. binding to CD4 chemikine receptor and co receptor

A

Gp120

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13
Q

Binding to CD4 chemokine receptor causes

A

Conformational change in gp120 - move aside exposing GP41

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14
Q

GP41 is made up of …

A

two heptad repeat domains, HR1 (tightly wound could) and HR2 (random chain - closest to virus)

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15
Q

How do the membrane come into contact?

A

H2 coils into h1, zipping together, punches a fusion pre into both membranes, allows HIV caspid to pass

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16
Q

Fuzeon mimics… Which has the what effect…

A

H2 region Of gp41

Prevents zipping so membranes never come into contact

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17
Q

Advantages of fuzeon

A
  • Revolutionary class of HIV therapy
  • unique mode of action - no cross resistance with other classes
  • Shows antiviral activity in vitro against wild-type virus as well as virus resistant to all three of the currently available classes of antiretroviral
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18
Q

Disadvantages of fuzeon

A

Treatment is £13000 a year

Administered by sub cut bd

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19
Q

Why this admin technique

A

Not orally bio, does not obey lipinksis rules

Many ionisable groups so rapidly excreted and endogenous proteases degrade so short half life

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20
Q

Problems with biologicals

A

Proteins and peptides are not good drug like molecules

21
Q

Why are we particularly concerned with extending half life?

A

Reduced cost of therapy

Improve quality of life

22
Q

Four main ways to produce biologicals….

A
  • Synthetically (peptides such as Fuzeon)
  • Human cell lines
  • Yeast cells (humanised)
    -Bacterial cells
23
Q

Compare yield and PTM of human, yeast, baeria

A

Human, retains PTM, low yeild
Yeast, retains PTM, better yeild
Bacterial does not retain PTM but has much better yield

24
Q

Most common method of production at the moment?

A

Bacterial

25
Q

Can only produce blogs also synthetically if…

A

Small insulin, fuzeon, 6000 DA.

Mab are often 100000

26
Q

Four PTMs

A

-Phosphorylation -Sulfation -Acylation -Glycosylation (addition of carbohydrates

27
Q

Two major gylcosylatiosn

A

O and n linked

28
Q

O linked is important …..

A

protein targeting to specific receptors

Eg blood antigens are o linked

29
Q

N linked is important becuase…

A

N-linked glycosylation plays important roles in protein regulation and serum half-life
N-linked carbohydrates play an important role in the PK properties of Biological Therapeutics

30
Q

Where can n link?

A

Asparagine

31
Q

Where can o link

A

Serene

32
Q

Why does adding a carb change the PK so much?

A

They are about the same size as the protein

33
Q

Can you repeat gylcosylatiosn in the lab?

A

No, variety of sugars attached in variety of ways, cannot repeat synthetically at scale

34
Q

Filgrastin is used…..

A

After chemo to replenish marrow (neutropenia)

35
Q

Class of filgrastin?

A

Filgrastim is a human granulocyte colony-stimulating factor (G-CSF).

36
Q

Filgrastin is a ….. aa protein made by

A

175
Recombinant DNA technology
18800 da

37
Q

Colony stimulating factors are…. Which act on…

A

Glycoproteins, which act on hematopoietic - binding and stimulating proliferation, differentiation commitment, and some end-cell functional activation

38
Q

Dose and frequency of filgrastin varies as per caner but.

A

Dosing ranges: - 3 – 70 micrograms DAILY

Each regim lasts between 7 days to 1 month.

39
Q

Elimination half life of filgrastin

A

3.5 hours

40
Q

Bacterial production of filgrastin by

A

E. coli with the human colony stimulating factor gene inserted

41
Q

How does the ecoli made filgrastin differ from human

A

PTM- non glycosylated

Hence short half life

42
Q

Pegylation

A

PEGylation, is a process of attaching the strands of polyethylene glycol (PEG) polymer to molecules
Typically 20-40 kDa

43
Q

Peg has lots of o in it, how does this work to our advantage?

A

Water surrounding increases size and mass of molecule even more, (reduced renal filtration and clearance of filgrastin) increases half life

44
Q

Immune advantage of PEG

A

Masks from immune system

reduced immunogenicity and antigenicity

45
Q

How do we achieve peg

A

incubation of a reactive derivative of PEG with the target macromolecule

46
Q

Five advantages of peg

A
  • Improved drug solubility
  • Reduced dosage frequency, without diminished efficacy with potentially reduced toxicity
  • Extended circulating life
  • Increased drug stability
  • Enhanced protection from proteolytic degradation
47
Q

Two commercial advantages of peg

A
  • Opportunities for new delivery formats and dosing regimens
  • Extended patent life of previously approved drugs
48
Q

Pegfilgrastim (NEULASTA)

A

covalent conjugate of recombinant methionyl human G-CSF (Filgrastim) and monomethoxypolyethylene glycol

49
Q

Admin of neulasata

A

Neulasta is administered by sub-cutaneous injection, ONCE A FORTNIGHT.
39kD … Increased half life

50
Q

Other Glycoslation ideas being explored

A

Synthetic
Albumin
Polysialic acid
Cellular gylcosylatiosn

Drug Disco (12 decks)

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