Lecture 11: Biologics; Proteins, Peptides and monoclonal antibodies

What are biologics

biologis are therpies that are in some way derived from another organism.

• example being monoclonal antibodies or insulin from pigs

What are the effects of usign bioligics/hwo do they differ from other things

1. Since they come from another organism, they tend to last longer than most standard drugs

2. They are not all identical, rather they are BIOSIMIALR

3. Temperature sensitive and subject to destruction in the GI tract.

What is Insulin’s active form? And the inactive form

Insulin’s actvie form is the monomer, AB form. In this monomer they are held together by disulfide bonds.

The inactvie form is the non monomer or the ACB subunit that is then broken into the AB form

How do we make insulin today?

We take the human gener, inject it via plasmids into the bacertia, bacteria grows the protien and then we inject it into the human body

How is insulin held in pancreati ccells

It is held as a Hexamer, where each subunit is held togtehr by Zn

Why si Zn addded as a preservative with injectable insulin

because it helps the monomers bind

How is Zn gotten rid of once it enters the bloostream?

What happens is that the Zn is dissolved in the blod adn the monomers are slowly freed and in turn able to do their job.

What is lispro (and how does it differ from its OG)

Lisrpo is an insulin analog that differs by one change in its AA sequence, specifically Proline (P) and Lysine (K) are switched

What are the effects of switching Proline and Lysine in Lispro/Insulin analog

Teh effects is that the protein is not held as tightly, so in turn the dissoaciation fo the hexamer happens QUICKER with lispro (3 hrs to 1hr WOW)

What are GLP1s

GLP1s are naturally occurring peptide hormones that regulate blood sugar and appetite, and act as signaling molecules.

What are the physiological effects of GLP1s

Increased satiety, energy consumption, insulin secretion and lipolysis

Decreased food intake, appetite, gastric emptying, GI motility, hepatic steatosis.

What is the mechanism behidn GLP1s

1. The GLP1 binds to the receptor, causing downstream effects in the cytosol

2. cAMP levels increase, leading to increased PKA activity where in which cAMP also activated Epac2 proteins

3. Activiation of Epac2 and PKa leads to release of Ca2+ into the cytosol, triggering th erelease of inusln from the insulin stroage granule

What are the main types of GLP-1 Drugs?

1. TIrzepatide (Mounjaro)

2. Semaglutide (Ozempic, Wegovy)

What is Tirzepatide (Mounjaro)

Mounjaro is a GLP-1 that is a duela antagonist that actviated both GLP-1 and GIP receptor, causing them to work in tandem and creates the Ca2+ release and insulin release

What is semaglutide (ozempic, wegovy)

a glp1 that is an agosnit and mikics th enatural horrmone and can be injected or orally afmisnitred

Why are most GLP-1s injected?

Beacsue if ingested, the protein would likely be degreaded int he small intestine

How is Ozempic (Semagltude) able to be ingested instead of injected like Mounjaro ?

SNAC tech that helps with absorption and permeabilty, whre in which a buffer is cloaking the protein, allowign for ti to survive the low pH of the small intestine.