Midterm

Question 1

What is the primary fxn of the RAAS?

Answer 1

regulation of bp

Question 2

Which are viable targets for antihypertensives acting on RAAS?

Answer 2

Renin
Angiotensin Converting Enzyme
Angiotensin II Type I Receptor
Mineralocorticoid Receptor (aldosterone receptor)

Question 3

What is the purpose of renin and what is the general mechanism by which it works?

Answer 3

Aspartyl protease cleaves angiotensinogen to convert to angiotensin I

Question 4

Why is renin a good target?

Answer 4

Renin catalyzes the rate-limiting step in the RAAS cascade

Question 5

How to -sartans work as antihypertensives?

Answer 5

Angiotensin narrows blood vessels, which increases bp and forces heart to work harder.
Angiotensin II receptor blockers help relax your veins and arteries to lower bp and make it easier for heart to pump blood.
Angiotensin II receptor blockers block action of angiotensin II.

Question 6

How do phosphodiesterase 5 (PDE5) inhibitors act as antihypertensives?

Answer 6

Vasodilators - allow cGMP (secondary messenger) to stay active and thus relax smooth muscle

Question 7

What is the rationale behind designing antagonists from agonists and what strategies are used?

Answer 7

Since agonists are known to already interact with target, they are a good starting point for design of antagonists
By adding more fxnl groups ,additional interactions can be used to alter the induced fit to inhibit target.

Question 8

Why did the chain extension of histamine along with guanidine result in antagonist activity?

Answer 8

The guanidine group interacts with both the agonist and antagonist area of the H2 receptor. However, the chain extension allowed the guanidine to specifically interact with the antagonist region.

Question 9

How do dipoles play a role in drug activity?

Answer 9

Proper alignment of dipoles in substrate and target will allow for stronger intermolecular interactions.

Question 10

Why are proton pump inhibitors superior over H2 antagonists?

Answer 10

They are downstream of the receptors that initiate the release of gastric acid (release of gastric acid is promoted by acetylcholine, gastrin, and histamine)

Question 11

What are the drug targets within the molecular pathway for adrenergic receptors?

Answer 11

1. Enzymes in the biosynthesis of noradrenaline
2. Vesicles carrying noradrenaline
3. Exocytosis of vesicles with cell membrane
4. Adrenergic receptor
5. Transport protein for noradrenaline
6. Metabolic enzymes
7. Presynaptic receptors

Question 12

What is the major difference between beta-1 and beta-2 adrenergic receptors

Answer 12

Beta-1 adrenoreceptors predominate in the heart.
Beta-2 adrenoreceptors predominate in the airways.

Question 13

How does insulin work?

Answer 13

Insulin binds to its receptor (receptor tyrosine kinase) which is activated to autophosphorylate then further phosphorylate other proteins to activate the signaling cascade which ultimately causes translocation of glucose transport protein to the cell surface

Question 14

Explain the difference between type 1 and type 2 diabetes

Answer 14

Type 1: caused by immune system attacking beta-islet cells in the pancreas, thus insulin is not produced.
Type 2: caused by decreased sensitivity of insulin, or less insulin produced.

Question 15

Why is teplizumab useful against type 1 diabetes but not type 2?

Answer 15

CD3-directed monoclonal antibody that is suspected to target the T-cells responsible for the attack on beta-islet cells.
Since T cells are not involved in type 2 diabetes, immunosuppresive therapy would not be useful for type2 diabetes.

Question 16

Briefly explain biguanides and incretin mimetics as diabetes therapeutics.

Answer 16

Incretin mimetics induce the pancrease to make more insulin biguanides limit the liver’s ability to make and release sugar

Question 17

What role does the FcRn (neonatal Fc receptor) have for mAb therapeutics?

Answer 17

This receptor interacts with the Fc portion of mAbs and allows for recycling back into circulation as opposed to catabolism

Question 18

How can engineering the Fc region enhance mAb therapies?

Answer 18

It can be utilized to alter PK properties through the FcRn and also induce stronger interactions with immune effector cells

Question 19

How can mAbs be utilized as effective anti-cancer agents?

Answer 19

Direct tumor cell killing can be elicited by receptor agonist activity, such as an antibody binding to a tumor cell surface receptor and activating it, leading to apoptosis (represented by the mitochondrion). It can also be mediated by receptor antagonist activity, such as an antibody binding to a cell surface receptor and blocking dimerization.

Immune mediated tumor cell killing can be carried out by the induction of phagocytosis; complement activation; antibody-dependent cellular cytotoxicity (ADCC); genetically modified T cells being targeted to the tumor by single-chain variable fragment (scFv); T cells being activated by antibody-mediated cross-presentation of antigen to dendritic cells; and inhibition of T cell inhibitory receptors, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA4).

Vascular and stromal cell ablation can be induced by vasculature receptor antagonism or ligand trapping (not shown); stromal cell inhibition; delivery of a toxin to stromal cells; and delivery of a toxin to the vasculature. MAC (membrane attack complex); MHC (major histocompatibility complex); NK (natural killer)

Question 20

What are typically considered antigens for mAbs?

Answer 20

Overexpressed receptors on cancerous cells, in tumor microenvironment, receptors with known oncogenic mutations.

Question 21

What is the theory behind ADCs?

Answer 21

The antibody can specifically target tumor antigens to allow for specific release of highly potent drugs.

Question 22

Concerning ADCs what are some of the design principles that are most important?

Answer 22

Linker should be stable enough to withstand circulation but still enable release of active drug

Drug should have proper physicochemical properties which enable uptake into neighboring tumor cells.

Question 23

Why is it necessary to have extremely potent drugs for ADCs?

Answer 23

ADCs typically have a DAR that is very low. Therefore, the drugs must induce an effect at very low concentrations.

Question 24

How can heterogeneity be improved for DAR?

Answer 24

Incorporate unnatural amino acids to have specific conjugation,

Utilize enzyme-directed conjugation

Utilize new chemistry to make use of disulfide bridges at hinge region without disrupting antibody structure.

Question 25

Explain why 3rd generation ADCs have greater therapeutic window than previous generations.

Answer 25

Improved chemistry has allowed for more homogeneous DAR, stable linkers, enhanced PK profiles, dual targeting, dual drug loading, more potent drugs.