1. Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue for Type II Diabetes
Jialin Liu

2. Type II diabetes
Diabetes mellitus type 2 (also known as type 2 diabetes) is a long-term metabolic disorder that is characterized by high blood sugar, insulin resistance, and relative lack of insulin.
Common symptoms include increased thirst, frequent urination, and unexplained weight loss.
Type 2 diabetes makes up about 90% of cases of diabetes

3. Insulin
Most people who have diabetes and take insulin need at least 2 insulin shots a day for good blood sugar control. Some people need 3 or 4 shots a day.
“I am better controlled with insulin, but I simply hate the injections, I wish I could get rid of them”. 
“I would do the impossible to avoid the injections, they are very inconvenient and because I am not very careful with changing the local of the injections, I am usually full of hard spots”.

4. Glucagon like peptide-1
What is it?
GLP-1 is an incretin hormone that simultaneously lowers blood glucose and body weight. It’s a promising therapeutic agent for treating type 2 diabetes (T2D). Physiologically, GLP-1 is secreted from the L-cells in the intestine as a response of meal ingestion.
How does it work?
The mechanism of action of GLP-1 is to stimulate insulin secretion, stimulate beta-cell function, increase beta-cell mass, and to decrease glucagon secretion, gastric emptying, and appetite.

5. Problems I
GLP-1 exists in 2 forms, one is the GLP-1 (7-36) amide form (which accounts for 80% of all circulating GLP-1) and the GLP-1 (7-37) form
DPP-IV cleaves the peptide bond of GLP-1 in Ala8-Glu9, and the resulting metabolite GLP-1(9–36)-NH2 is found to have 100-fold lower binding affinity compared to the intact peptide. The metabolite also exhibits negligible agonistic activity (>10000-fold decrease)

6. Alanine substitution
Glu9 is important for receptor binding , much work has focused on Ala8.
Alanine (Ala)
Glycine (Gly)
Threonine (Thr)
Serine (Ser)
2-Aminoisobutyric acid (Aib)

7. Insulin secretion by the isolated perfused
porcine pancreas during infusion of 1 nmol/l GLP-1 (7±
36)amide or N-terminally modified analogues.
The lower the IC50, the more potent your molecule is.,the lower the IC50 of your drug, the less you need to achieve the desired effect

8. Problems II
Kidneys clear GLP-1 quickly. The half-life of GLP-1(7−36)amide in humans has been determined to be 1.5 min after iv administration and 1.5 h after sc administration.

9. Half-life extension
Human serum albumin (HAS) is the most abundant plasma protein, highly soluble, very stable and has an extraordinarily long circulatory half-life (~20 days).
Albumin

10. Serum albumin is a fatty acid transporter
 Albumin acts as main fatty acid binding protein in extracellular fluids. Plasma albumin possesses about 7 binding sites for fatty acids with moderate to high affinity.

11. Semaglutide
The plasma half-life was 46.1 h in mini-pigs following i.v. administration. GLP-1 was about 1.5 min.
Aib substitution
Fatty acid
Linker

12. Length of fatty acid

13. Length of linkage

14. References:
Bell, G. I., Santerre, R. F., & Mullenbach, G. T. (1983). Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature, 302(5910), 716–718.
Holst, J. J. (2007). The physiology of glucagon-like peptide 1. Physiological Reviews, 87(4), 1409–
Lovshin, J. A. (2017). Glucagon-like Peptide-1 Receptor Agonists: A Class Update for Treating Type 2 Diabetes. Canadian Journal of Diabetes, 41(5), 524–
Madsen, K., Knudsen, L. B., Agersoe, H., Nielsen, P. F., Thøgersen, H., Wilken, M., & Johansen, N. L. (2007). Structure−Activity and Protraction Relationship of Long-Acting Glucagon-like Peptide-1 Derivatives:  Importance of Fatty Acid Length, Polarity, and Bulkiness. Journal of Medicinal Chemistry, 50(24), 6126–
Manandhar, B., & Ahn, J.-M. (2015). Glucagon-like peptide-1 (GLP-1) analogs: Recent advances, new possibilities, and therapeutic implications. Journal of Medicinal Chemistry, 58(3), 1020–