Peptide and Peptidomimetic Drugs

Question 1

what are the problems with peptides and proteins as drugs?

Answer 1

• oral route: enzymatic hydrolysis of peptide bonds in GI tract, kidney + liver
• other routes: metabolism happens in lungs, nasal mucosa + in blood
• compactness of full sized proteins makes them more resistant than small proteins + polypeptides
• many peptides = hydrophilic + display poor passage through lipid membranes

Question 2

what is pepsin?

Answer 2

endopeptidase that cleaves at carbonyl side aromatic (phe, tyr, trp) + acidic (glu, asp) residues

Question 3

what is the pH of the small intestine?

Answer 3

7

Question 4

what does the pancreas secrete?

Answer 4

trypsin, chymotrypsin + elastase

Question 5

where does trypsin cleave?

Answer 5

carbonyl side of basic (lys + arg) residue

Question 6

where does chymotrypsin cleave?

Answer 6

aromatic (tyr, phe, trp) residues

Question 7

where does elastase cleave?

Answer 7

small, statically unhindered residues (ala, gly, ser)

Question 8

how can you decrease proteolysis?

Answer 8

• replace selected L-AA with D counterparts
• change primary amide to secondary amides at key cleavage sites
• reversing peptide bond / use of pseudo peptides

Question 9

what is leuprolide an analogue of?

Answer 9

gonadotropin releasing hormone

Question 10

how can we get around the problem that peptides pose as drug candidates?

Answer 10

• non-hydrolysable peptide mimic that binds to active site will act as comp inhibitor of hydrolysis of real substance
• replacement of natural mol with lipophilic moieties will inc membrane permeations + inc bioavailability

Question 11

what does the use of unnatural amino acids lead to?

Answer 11

higher affinity

due to target binding sites not reached by natural substrate

Question 12

what is RGD?

Answer 12

one letter code for the sequence arginine-glycine-aspartic acid

Question 13

what is RGD used for?

Answer 13

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

by blocking the binding, platelet aggregation = prevented

valuable in treatment of stroke + heart attacks

Question 14

what is somatostatin? (GHIG)

Answer 14

14 residue peptide macrocyclised through cys-cys disulphide bridge

Question 15

what are thyrotropin-releasing hormones and their derivatives leads for?

Answer 15

treatment of Alzheimers disease and other cognitive disorders

Question 16

combinatorial approaches to drug discovery?

Answer 16

use high throughput screening assays to test for level of activity against multiple targets

Question 17

rational approaches to drug discovery?

Answer 17

design drugs to fit receptor / active site

test against selected targets

Question 18

HIV protease inhibitors?

Answer 18

• important for formation of mature infectious virions

- cleaves viral polyproteins —> functional viral proteins

Question 19

describe the ‘lead for inhibitor design’?

Answer 19

• proteases cleave amide bonds in other peptides
• HIV protease selective for this peptide sequence
• design mimic with no cleavable peptide

Question 20

what does the protease mechanism use?

Answer 20

bound water molecule in active site

proceeds via key diol intermediate