Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

PHRM3041 > Peptides/ proteins > Flashcards

Peptides/ proteins Flashcards

1
Q

Why are peptides and proteins injected IV or SC?

A

due to enzymatic and pH-dependent degradation in GIT,

low epithelial permeability and instability during formation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Common routes of admin of peptide/proteins

A

nasal cavity (rich blood supply)
buccal cavity
rectal cavity (bypass first metabolism)
transdermal

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What is good and bad in biological pharmaceuticals (like peptides)?

A

It has the molecular characteristics to promote interaction with target

BUT
it lacks the ability to reach the target

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What are the issues in peptide/proteins?

A

stability and barriers

They are highly polar, soluble and rapidly excreted (short half life)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

why are peptides/proteins substrates for peptidases?

A

because they cannot cross biological barriers very well (due to N-terminal amino, C-terminal carboxy, and side chains COOH,NH2,OH)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Challenges in delivery of biological pharmaceuticals

A

Physical (BBB, GI)
Chemical (pH change)
Biochemical (digestive enzymes/ flora in GI)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What happens in physical instability (4 types)

A

proteins lose 3D structure

Aggregation, adsorption, denaturation, preciptation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Aggregation

A

This is irreversible (self-association is reversible - insulin is selfassociated then dissociated after SC dosing)

When it is too acidic/ too much salt (negative charge), the interaction between negative and positive charges in the folded polypeptides become weak, so it falls out (conformation change) and bind to each other with similar shape
They drop out fluid and cause precipitation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Denaturation

A

Reversible or irreversible
Disruption of secondary and tertiary structure of protein
By heating/cooling/freezing/pH extremes/ contact with denaturants

two CYS-SH bond together and these can unfold leading to adsorption, aggregation, precipitation, chemical reactivity

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What are some examples of irreversible denaturation in physical instability?

A

increase in ionic strength of protein solution (neutralisation of surface charge for repulsion so aggregate formation)

Increase in temperature increases flexibility/ unfolding
(collision increases and aggregate formation)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Adsorption

A

Insulin frosting on the glass surface

leads to further denaturation and precipitation (physical blocking of delivery ports)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

How to prevent protein adsorption?

A

Avoid glass containers
Coat glass container with another protein
Add surfactants (sticks to glass)
Minimise air exposure (decrease protein denaturation)
Agitation or application of other shear forces can cause denaturation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

What happens in chemical instability of peptides/proteins?

A

covalent modification in protein or AA residue to make new molecules via bond breaking/forming/rearrangement/ substitution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What are the chemical instabilities?

A

deamination, oxidation, racemisation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What happens in deamination

A

hydrolysis of side chain in glutamine and ASPARAGINE
to make COOH
(acid catalysed hydrolyssi –> base structure comes off and the acidic group is attached by H-bonds)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Oxidation

A

major cause of protein degradation

Occurs on side chain of His, Met, Cys, Trp, Tyr

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Racemisation

A

Base- catalysed racemisation occurs in all AA residues EXCEPT GLYCINE (chiral at carbon atom with the side chain - fixed in space)

18
Q

What are the biochemical barriers in delivery of peptides?

A

Celluar (epi/endothelial), metabolic, immunological, lymphatic drainage

19
Q

Difference between epi/endothelia

A

epi= covering cutaneous, mucous, serous SURFACES

endo - lining membrane of cavities (heart/lung)

20
Q

GI barriers for oral delivery

A

intestinal lumen, mucosa, liver, chemical/physical instability by acids, epithelial barrier, enzymatic barrier (proteases cause hydrolysis of peptide bonds)

21
Q

Biochemical barrier - enzymes

A

most degradation by peptides need contact with brushborder membrane or uptake into intestinal mucosal cells

Brush-border peptidases
(active mainly against tri/tetra and higher peptides)

Intracellular peptidases (predominantly against DI)

Endopeptidases (cleave internal peptide bonds, for lage peptides or with blocked ends)

Exopeptidases (cleave one or more residues from terimini of peptide)

22
Q

Biochemical barier - efflux system - P-gp

A

MAJOR BARRIER by limiting absorption

P-glycoprotein (multi-drug resistance)
Acts on atp-dependent efflux pump, reducing intracellular accumulation/ transceullar flux of drugs

Restrict transcellular reflux of some molecules to GIT

23
Q

Physical barrier - intestinal mucosa structure

A

Paracellular (between)

transcellular (through) -

24
Q

What is the main physical barrier?

A

tight junctions in CNS

25
Q

What is paracellular pathway

A

between cells

  • aqueous channel, extracellular route across EPIthelia,
  • Passive, driven by graidents and hydrostatic pressure
  • increase HYDROPHILICITY
  • Generally by water and small solutes
26
Q

What is transcellular pathway

A

Through the cells for intestinal absorption

  • Passive (rare), carrier mediated (substrate specific), vesicular
  • increase LIPOPHILICITY,
  • improve reabsorption
27
Q

What are the vesicular mechanisms in intestinal absorption in transcellular pathway?

A
  • endocytosis when peptide is too large to be absorbed by di/tri transporters
  • pino (fluid filled endocytosis, no interaction between polypeptide, apical membrane)
  • phago
  • receptor mediated endocytosis (binding of peptides, proteins to plasma membrane before getting into vesicles)
  • Passive diffusion
28
Q

Physical barrier: mucous function

A

coat the muosa
lubricate and protect
effect peptide absorption (washes away)

29
Q

Delivery to CNS involves 3 factors, they are

A

BBB, CNS entry, associated factors, transporters

30
Q

What is the distance of mean inter-capillary distance in brain?

A 
almost 40um (very small)
instantaneous solute equilibration throughout the brain for small molecules (eg. glucose)
31
Q

Does peptide/protein go through BBB?

A

No,
tight junctions in brain capillary endothelium
brain capillary endothelial cells contain few pinocytotic vesicles

32
Q

Cerebral capillary transport

A
  • Tight junctions (seal pathway between the capillary cells) - arachnoid cells line the meninges
  • lipid membranes (barrier to water-soluble)
  • ions channels/carriers
  • enzymatic barrier (remove molecule from blood)
  • efflux pumps (extrude fat-soluble molecules)
33
Q

Transport mechanisms in the brain

A

paracellular :diffusion of small water soluble ones
transcellular lipophilic: diffusion of lipid soluble ones
saturable transport: transfer of essential POLAR solutes like glucose, AA, nucleosides
Specific receptor-mediated endocytosis: insulin, transferrin, cytokines
Adsorptive endocytosis: cationisation of albumin
Effux transport: pumping out faster than accumulating

34
Q

Carrier mediated transport across BBB

A

Monoclonal antibodies to transferrin receptor (act as dimer, it has high affinity binding sites for Fe2+ ions, most of the receptor in the extracellular space)

Glucose - GLUT1 (smaller)
- Na+ independent

35
Q

Solution to delivery problems - what are the 3 broad approaches of chemical modifications?

A
  1. Non-peptide natural product that mimics/antagonises biological activity (Ang ii antagonist)
  2. use a novel route/ co administer with enzyme inhibitor
  3. Develop a peptidomimetic that resembles target protein but reduce metabolism and optimise activity
36
Q

How to limit peptide bond hydrolysis in vivo

A
  1. Add steric bulk form (Alkyl group or 4o amino acid - to increase incidence of CIS configuration of amide bond
    - -> conformation/steric changes
  2. Replace the scissile (RNH-COR) bond altogether - in ACE, renin
    - -> subtle conformational changes
  3. Modify peptide conformation so that it s no longer recognised by proteases (constraining peptide backbone)
4. Cyclize peptide
(use covalent linkages)
- amide/ side chains(NH2, COOH)
--> conformational constraint
- simple and effective
37
Q

Enhancement of passive diffusion cross intestinal mucosa

A

sufficient hydrophilicity
highly potent and hydrophilic peptides
(more lipophilic –> more interaction with cell membrane)

38
Q

Enhancement for transcellular pathway

A

need an optimal lipophilicity

  • energy necessary for a solute to enter from aqueous phase to membrane phase
  • decrease in h-boding potential for peptide permeation improves transcellular passage
39
Q

Minimisation of substrate activity towards intestinal efflux systems

A

difficult to identify characteristic structural element needed for substrate activity
LIPHILICITY - substrate feature
WATER SOLUBILITY

high hydrophobic drugs that are sparingly soluble in water are not substrates

40
Q

Inhibition of efflux pumps

A

co-administer 2nd generation inhibitor, lacking pharmacological activity (verapamil (R-isomer)

PHRM3041 (9 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions