In Novo’s Own Words: Degradation of Amylin Analogs Such as Cagrilintide (and How to Test For It)

I must have conjured him when I made this remark in another thread just yesterday:

that particular type you sometimes see around these parts—people who consider themselves of above-average intellect so pop off endlessly using lofty language in order to boost that ego. This type loves to cosplay as academics when they "publish whitepapers" and such. Probably not grifters, just self-rightious guys with a savior complex
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exploitedworkerbee said:
@secretweapon sorry who are you? You just joined today to post this, and your conclusion is that people who disagree with your assessment have ulterior motives?
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The other significant omission you made was the "based on a test" part, referring to anyone pushing a test result conducted without using SEC at a bare minimum.

This is not just about the opinions held by randos.
 
secretweapon said:
The other significant omission you made was the "based on a test" part, referring to anyone pushing a test result conducted without using SEC at a bare minimum.

This is not just about the opinions held by randos.
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Don't they speak to the different pH levels (4 and 7.5) while subjecting Cagri to mechanical stress?

And they couldn't form any fibrils? Are you saying that this is incorrect and they didn't use the right equipment to test for formation of harmful molecules?
 
brentm said:
View attachment 4063

Don't they speak to the different pH levels (4 and 7.5) while subjecting Cagri to mechanical stress?

And they couldn't form any fibrils? Are you saying that this is incorrect and they didn't use the right equipment to test for formation of harmful molecules?
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Fibrils are of secondary importance in this discussion. You could almost leave them out of it.

The real toxic species are oligomers. Oligomers eventually become fibrils, but they raise a lot of hell on the way.

And yes, they subjected many different amylin analogues to mechanical stress to see which ones fibrillate. Fibrils are a lot easier to detect than oligomers.

Two important points about those tests:

1. Almost every single amylin analogue fibrillated at pH 7.5 (including cagrilintide). The only one that didn't was rejected for low potency.
2. Many of the amylin analogues did *not* fibrillate at pH 4.0 (not just cagrilintide).
 
Really wish we'd spend more time focused on what the OP has written and backed up with scientific evidence, rather than the OP himself.

Because this shit is pretty scary, I know we're used to all sorts of peptides of unknown benefit or harm, but here it seems we have a peptide with a likely known harm.
 
penewbie said:
Really wish we'd spend more time focused on what the OP has written and backed up with scientific evidence, rather than the OP himself.

Because this shit is pretty scary, I know we're used to all sorts of peptides of unknown benefit or harm, but here it seems we have a peptide with a likely known harm.
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I sure thought that was strange. I took myself out of the equation by making it all about direct Novo quotes and people still want to shoot the messenger.
 
Yay-Z1 said:
Could yall be confusing Cagri with Pramlintide
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Here's something I wrote. Does it answer your question?

Cagrilintide retains the three proline substitutions that pramlintide made to human amylin to make it resistant to fibrillation, but it has four more improvements:
  1. While pramlintide has a short half-life and must be dosed multiple times per day, researchers created a long-acting version that allows once-weekly dosing by adding a long fatty acid chain to the pramlintide molecule. The fatty acid allows cagrilintide to bind to albumin (a protein in the blood). When bound to albumin, cagrilintide is cleared from the body more slowly.
  2. Researchers made cagrilintide resistant to a chemical reaction called deamination, which can break down the molecule, by replacing the asparagine amino acid (Asn) at position 14 with glutamic acid (Glu). Note: deamiNation is a distinctly different process from deamiDation (the latter leading to fibrillation).
  3. They also made cagrilintide more soluble, meaning it dissolves more easily in water, by replacing valine (Val) with arginine (Arg) at position 17.
  4. While pramlintide is a single-hormone agonist for amylin receptors, cagrilintide is a dual-hormone agonist for both amylin and calcitonin receptors. This is due to proline (Pro) being replaced by Tyrosine (Tyr) at position 37.
Those are the only four changes made to pramlintide to create cagrilintide. One important thing to note is that none of the changes made pramlintide more resistant to fibrillation or more stable at a higher pH. This means that any research on the pH requirements or fibrillation of pramlintide will also apply to cagrilintide.
 
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