Long-acting GLP-1 analogue #1
Category
ID
NNC0090-1170
Amount per vial
1000 nmol (research grade purity)
NNC0090-1170 (also known as liraglutide) is a GLP-1 analogue with 97% sequence homology to human GLP-1 that binds to and activates the GLP-1 receptor. Compared to native GLP-1, NNC0090-1170 have been designed to be long-acting in vivo. The main mechanism for the extended half-life is albumin binding. Furthermore, the NNC0090-1170 has a delayed uptake from the subcutis.
GLP-1 action is mediated via a specific interaction with GLP-1 receptors, leading to an increase in cyclic adenosine monophosphate (cAMP). GLP-1 stimulates insulin secretion in a glucose-dependent manner. Simultaneously, GLP-1 lowers inappropriately high glucagon secretion, also in a glucosedependent manner. Thus, when blood glucose is high, insulin secretion is stimulated and glucagon secretion is inhibited. Conversely, during hypoglycaemia GLP-1 diminishes insulin secretion and does not impair glucagon secretion. GLP-1 is a physiological regulator of appetite and food intake and the GLP-1 receptor is widely expressed in the brain.
Category
ID
NNC0090-1170
Amount per vial
1000 nmol (research grade purity)
| Property | NNC0090-1170 | GLP-1 (7-37)-OH |
| MW (Da) | 3751.2 | 3355.7 |
| pI (calculated) | 4.5 | 5.5 |
| Sequence substitutions (compared to
reference) | 26K(C16-gGlu),
34R | |
| Extinction coefficient (calculated,
280 nm) | 6990 | 6990 |
Figure 1
2D sketch of NNC0090-1170. NNC0090-1170 has a C16 fatty acid chain which is attached via a gamma glutamic acid linker to lysine at position 26. In addition, lysine is replaced with arginine at position 34. The fatty acid side chain enables reversible binding to serum albumin in the blood stream, which increases the half-life of the molecule.
Figure 2
3D model of NNC0090-1170 based on a crystal structure and modelling of the fatty acid side chain.
Figure 3
2D sketch of human GLP-1 (7-37)-OH (NNC0113-0007).All in vitro data are based on in vitro assays using cloned human GLP-1 receptors expressed in baby hamster kidney cells. Since albumin binding is a key mechanism for the design of NNC0090-1170, the apparent affinity and potency will be very dependent on whether the assays contain albumin or not. See the Lau et al. 2015 reference listed in the reference section for further details on the experimental setup of the in vitro assays that have been used to generate the data in the table.
| hGLP-1R binding (IC50, nM +/- SEM) | ||
| Compound
| 0% HSA
| 2% HSA
|
| GLP-1 (7-37)-OH | 0.19 +/- 0.03 | 0.10 +/- 0.02 |
| NNC0090-1170 | 0.11 +/- 0.02 | 4.78 +/- 1.01 |
| hGLP-1R potency (EC50 pM, +/- SEM) | ||
| GLP-1 (7-37)-OH | 16.2 +/- 0.9 | |
| NNC0090-1170 | 8.5 +/- 0.7 | |
The terminal half-life of NNC0090-1170 is around 14 h in pigs while shorter in mice, rats, rabbits and monkeys (4-8 h).
NNC0090-1170 has been evaluated in several diabetic and obese animal models. NNC0090-1170 shows a dose-dependent and long-lasting anti-hyperglycaemic effect in ob/ob and db/db mice. The mean area under the curve (AUC) for blood glucose is dose-dependently reduced after a single subcutaneous injection of NNC0090-1170 (30, 100, 300 or 1000 ug/kg). In db/db mice, the ED50 for lowering of blood glucose (6 hours post dosing) is estimated to be approximately 24 ug/kg following an acute dose. With twice daily administration of 100 ug/kg NNC0090-1170 for two weeks, blood glucose AUCs were significantly reduced in ob/ob mice. These anti-hyperglyeamic effects are also observed in db/db mice treated for 15 days with NNC0090-1170 (200 ug/kg twice daily s.c.).
In young ZDF rats, 6 week treatment with NNC0090-1170 (30 and 150 ug/kg twice daily s.c.) reduces blood glucose levels and insulin levels following a glucose tolerance test. In candy-fed rats, NNC0090-1170 (0.2 mg/kg, twice daily, s.c.) reduces food intake and subsequently weight gain, especially fat mass.
When administering NNC0090-1170 to animals it is necessary to do dose titrations. A good dose for pharmacological experiments could be 1 mg/kg once daily titrated up from 0.1 mg/kg to 0.3 mg/kg to 1.0 mg/kg.
If using ELISA to detect NNC0090-1170 in your samples, ensure to use a kit that is able to detect this analogue of GLP-1.