Long-acting glucagon analogue

Category

Glucagon

ID

NNC9204-0043

Amount per vial

1000 nmol

Glucagon is s a 29 amino acid residue peptide hormone produced by the alpha-cells in the pancreas. Together with insulin it regulates blood glucose levels. It stimulates release of glucose from the liver at low blood glucose levels by increasing gluconeogenesis and glycogenolysis, and by suppressing glycolysis. Glucagon is used to treat insulin-induced severe hypoglycemia.

NNC9204-0043 is a long-acting glucagon analogue.

Category

Glucagon

ID

NNC9204-0043

Amount per vial

1000 nmol

PropertyNNC9204-0043Native glucagon
MW (Da)4138.63482.7
pI (calculated)4.96.4
Sequence substitutions (compared to reference)17K, 18K, 21E, 24K(2xOEG-gGlu-C18 diacid), 27L-
Extinction coefficient (calculated, 280 nm)84808480

Figure 1

2D sketch of the structure of NNC9204-0043. The compound has the following sequence substitutions compared to native glucagon: 17K, 18K, 21E, 24K(2xOEG-gGlu-C18 diacid), 27L.

Figure 2

The sequence of native glucagon.
In vitro potency and receptor binding data for NNC9204-0043 and native glucagon (unpublished data).

The binding affinity to human GCGR was measured by the ability of the compounds to displace 125-iodine-labelled glucagon from baby hamster kidney (BHK) cell plasma membranes stably expressing the human GCGR in a scintillation proximity assay (SPA) setup. The in vitro potencies were determined by luciferase assays using BHK cells stably transfected with the human GCGR and CRE luciferase. Since albumin binding is a key mechanism for the design of NNC09204-0043, be aware that the apparent affinity and potency will be very dependent on whether the in vitro assays contain albumin or not.

CompoundPotency
No HSA 
(EC50, pM ± SEM)
Potency
1% HSA 
(EC50, pM ± SEM)
Native glucagon9.8 ± 0.7 (n=194)8.4 ± 0.7 (n=94)
NNC9204-00437.1 ± 0.6 (n=52)440 ± 57 (n=32)


Receptor affinity
No BSA
(IC50, nM ± SEM )
Receptor affinity
0.2% BSA
(IC50, nM ± SEM )
Native glucagon
0.63 ± 0.02 (n=142)
0.33 ± 0.01 (n=138)
NNC9204-0043
0.45 ± 0.04 (n=42)
31 ± 2.7 (n=40)
BSA: bovine serum albumin; HSA: human serum albumin

The terminal half-life of NNC9204-0043 is 5-6 h following s.c. administration of a single 3 nmol/kg dose in mice.

The reference compound to NNC9204-0043 is native glucagon (NNC0025-8000). Please indicate (with a check mark at ‘Please add the reference compound if available) during your compound request if you would like to have native glucagon (NNC0025-8000) included in your shipment.
Peptides and proteins have a tendency to adhere to glass and plastic surfaces. This may at low concentration impact the actual amount in solution. To minimize this unspecific adherence, adding detergents or inert proteins like e.g., ovalbumin or other serum albumins to the solution can minimize this phenomenon. In case albumins are added to peptide/protein solutions, ensure that the albumins are free of any proteases, but be aware that it will affect the apparent potency and affinity in in vitro assays in case a fatty acid is attached to the compound. The freeze-dried material should be stored at -18C. NNC9204-0043 can be dosed in vivo in a formulation vehicle containing 50mM sodium phosphate, 145mM propylene glycol, (0.007% polysorbate 20 if concentrations are so low that adsorption to vials may affect the concentration), pH 7.4. Stability in aqueous media is poor thus formulations should be used fresh. For in vitro it is recommended to dissolve human glucagon in 100% DMSO (e.g at a concentration of 300 uM) and keep at max 5C.