Peptide & Peptidomimetic Drugs

Question 1

List some problems with peptides & proteins as drugs

Answer 1

• Oral admin: enzyme hydrolysis of peptide bonds in GI, kidney & liver
• Other routes: metabolism in lung, nasal & mucosa
• Compact globular nature makes them more resistant
• Many peptides/proteins are significantly hydrophilic & display poor passage through lipid membranes

Question 2

List peptidases in the GI tract

Answer 2

• Stomach: ph 2, gastric mucosa secretes pepsin
• Small intestine: ph 7, encounters trypsin, chymotrypsin and elastase all secreted by pancreas
• Trypsin: cleaves at carbonyl side of basic residue
• Chymotrypsin: cleaves at aromatic residues
• Elastase: cleaves at small, sterically unhindered residues

Question 3

What does pepsin do?

Answer 3

An endopepsidase that cleaves at the carbonyl side of aromatic and acidic residues

Question 4

What are the aromatic, basic and acidic residues?

Answer 4

• Aromatic: Phe, Tyr & Trp
• Acidic: Glu, Asp
• Basic: Lys, Arg

Question 5

What are sterically unhindered residues?

Answer 5

Ala, Gly & Ser

Question 6

Small units are attacked further from first wave of digestion by what?

Answer 6

Carboxy & aminopeptidases

Question 7

List how to decrease proteolysis

Answer 7

• Replace selected L-amino acids with their D-counterparts
• May increase resistance to proteolysis while retaining intended activity
• Change primary amide to secondary amides at key cleavage sites
• Others include reverse the peptide bond, or use of pseudo peptides
• Co-admin of protease inhibitors and permeation enhancers aids in nasal delivery

Question 8

Give an example of a gonadotropin releasing hormone

Answer 8

Leuprolide

Question 9

What do peptidomimetics do?

Answer 9

• Mimic the structures of particular peptides

- This can fool a receptor into thinking it is binding for the actual peptide and induce the same bio effect

Question 10

What would a non-hydrolysable peptide mimic expect to act as?

Answer 10

A competitive inhibitor of the hydrolysis of the real substrate

Question 11

Replacement of non-pharmacophoric polar sections of the natural molecule with lipophilic moieties will what?

Answer 11

Increase membrane permeation and increase bioavailability

Question 12

What can the peptide backbone be replaced with?

Answer 12

Alternate atoms/groups

Question 13

What do the phenylalanine groups differ in?

Answer 13

Lipophilicity

Question 14

Structural extension results in what?

Answer 14

Higher affinity

Question 15

What is RGD a one letter code for?

Answer 15

The sequence arginine-glycine-aspartic acid

Question 16

What does this motif of RGD block?

Answer 16

Block binding of fibrinogen to its receptor, glycoprotein IIb/IIIa

Question 17

By blocking this binding what is prevented?

Answer 17

Platelet aggregation which is valuable in the treatment of stroke & heart attacks

Question 18

Growth hormone is a residue peptide through what disulphide bridge?

Answer 18

Cys-Cys

Question 19

What does glucose scaffold analogue of a small cyclic peptide agonist display?

Answer 19

Effective GH inhibition in cultured rat anterior piuitary cells

Question 20

What do the compounds & derivatives of thyrotropin releasing hormone lead to?

Answer 20

Treatment of alzheimer’s disease and other cognitive disorders

Question 21

List other common ways to change a peptide backbone: pseudopeptides?

Answer 21

• Isoteric replacement
• Chain extension
• Amide isoteres

Question 22

Some peptides & proteins are administered _____ as ______

Answer 22

unchanged

drugs

Question 23

For most peptides with biological activity, ADME profiles do what?

Answer 23

prohibit their use

Question 24

What is a pharmacophore?

Answer 24

binding subunits in 3-dimensional space

Question 25

What does the replacement strategy do?

Answer 25

Maximises hydrolytic stability and may be used to improve passage of drug through biological membranes through fine tuning lipophilicity

Question 26

List selected drug discovery approaches

Answer 26

• Combinatorial: produce 100’s using SPOS, use high throughput screening assays to test for level of activity against multiple targets
• Rational
  Design drugs to fit receptor
  Test against selected targets

Question 27

What is the HIV protease inhibitor for?

Answer 27

• Crucial for formation of mature infectious virions

- Cleaves viral polyproteins to functional viral proteins

Question 28

Proteases cleave amide bonds where?

Answer 28

in other peptides

Question 29

What does a protease mechanism lead to?

Answer 29

• Reaction uses a bound water molecule present in active site
• Proceeds via a key diol intermediate

Question 30

Solid Phase Organic Synthesis is widely used in what?

Answer 30

Combinatorial chemistry

Question 31

What are two major methods of drug discovery?

Answer 31

• Combinatorial chemistry

- Rational Drug Design

Question 32

How can clinical drugs be developed?

Answer 32

A detailed knowledge of the chemistry of a protein target

Question 33

Which of the following enzymes limits the ability of peptide-based therapeutics to be successfully delivered orally?
	A	Chymotrypsin
        B	Elastase
	C	Trypsin
	D	All of the above
	E	None of the above

Answer 33

D All of the above

Question 34

Which rules would suggest that a decapeptide would fare poorly if delivered by an oral route?
	A	Baldwin’s
	B	Lipinski’s 
	C	Markovnikov’s 
	D	Woodward-Hoffmann’s
	E	Zaitsev’s

Answer 34

B Lipinski’s

Question 35

What is generally considered to be the most successful route of delivery for a peptide based therapeutic?
	A	Buccal
	B	Oral
	C	Pulmonary
	D	Parenteral
	E	Transdermal

Answer 35

D Parenteral