Drug Design (I)

Question 1

What are two reactions that render peptides as drugs chemically unstable?

Answer 1

Hydrolysis/oxidation

Question 2

Why are peptides as drugs physically instable?

Answer 2

Solubility issues

Too big to be orally available, need to be injected via IV

Question 3

Why are peptides used as drugs despite their weaknesses?

Answer 3

Their strengths are worth it

Good efficacy, safety/tolerability
High selectivity/potency
Predictable metabolism
Shorter time to market
Lower attrition rates

Question 4

How are peptide drugs discovered?

Answer 4

Traditional structure-based design

Ala scan for essential AAs, substitution of labile AAs, Structure-Activity Relation (SARs) EC50, etc

Question 5

What are 4 common peptide modifications?

Answer 5

AA shortening (smaller = better)

Cyclization (more stable, prevention from exopeptidase and endopeptidase)

Unnatural AAs (D conformation, Beta AAs, N-methylated AA, isosteres)

Glycosylation, PEGylation, etc (standard peptide mods

Question 6

What are 2 examples of peptidomimetics seen in class?

Answer 6

Consolidation of Beta turns so they’re less floppy (mimicked by cyclic peptides/unnatural AAs)

Stapled peptides (Alpha helices with extra linker to keep helices stable on their own)

Question 7

What is a property of cyclic peptides, notably bicyclics?

Answer 7

Very stable (if it interacts with its target, it will be very potent)

Question 8

What was found out about most venomous peptides in nature?

Answer 8

They are cyclic (Cys creates cyclic bonds)

Question 9

What is a less common feature of carbohydrates discussed in class in the context of Irritable bowel disease?

Answer 9

Glycosylation is one the most common protein modifications

First things you see as you a cell are carbohydrates

Question 10

What are common properties of carbohydrate drugs?

Answer 10

Lots of hydroxyls and sulphates

Charged, very polar

Question 11

What is an issue of carbohydrate drugs and why does that not matter?

Answer 11

Too polar to cross membranes, but usually the target is the blood so they don’t need to

Question 12

How are mannosides useful against UTIs?

Answer 12

Special strand of E.Coli expresses FimH which binds to the mannose residues presented on bladder cells

Mannosides have higher affinity to FimH, disrupt links

Question 13

How does EB8018 treat IBD?

Answer 13

By disrupting FimH on regular bacteria that trigger an immune response

Question 14

How does Zanamivir act as a potent neuraminidase inhibitor?

Answer 14

Mimic of transition state, disrupts equilibrium

Modified hydroxyl group (increases affinity 10k x)

Question 15

Why are Bioisosteres useful?

Answer 15

Can change properties of drug without changing affinity

Or to get around patents

Question 16

What was the problem with inorganic pyrophosphate as a drug against osteoporosis, and how was it modified to be more effective?

Answer 16

P-O-P link cleaved easily, very short half-life

Modified P-RCR-P (generic bisphosphonate) depending on R groups half life rose drastically

Question 17

How do organic bisphosphonates work? Is oral administration viable? Why?

Answer 17

Inhibition of FPPS, in turn inactivates Osteoclasts thus preventing bone breakdown

Can be used orally because it’s extremely potent (a minute amount can still have a therapeutic effect)

Question 18

How does Fluorine act as a bioisostere?

Answer 18

(F & H have roughly the same size but completely different electric properties)

F tends to pull electrons towards it, F-C bonds tend to be VERY hard to break (prolongs metabolism)

A F atom in a certain position can fix a small molecule in a potentially more useful conformation

Can also scan for F in PET

Question 19

How was Fluorination used to treat the Fentanyl crisis?

Answer 19

Fluorinated fentanyl is nontoxic, shifted pKa to be only effective in inflamed tissues

Same analgesic effects with fewer side effects typically seen in opioids

Question 20

There is virtually no difference between H and D, why is it used as a bioisostere? (in a way that is not patent circumvention)

Answer 20

C-D bonds are slightly more stable than C-H

If the metabolism of a drug requires the breakdown of C-H bonds, swapping them for C-D can limit that rate

Question 21

What bioisostere of an amide can you use to make a soft drug?

Answer 21

esterization