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

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

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”.

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.

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)

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)

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

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.

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

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.

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

Length of fatty acid

Length of linkage

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