Fig. 1: Functional principle and 3D model of NNC2215.
From: Glucose-sensitive insulin with attenuation of hypoglycaemia
a, NNC2215 is an insulin molecule with a glucose-sensitive switch. At increasing glucose concentrations, the switch equilibrates towards an open state and the insulin receptor affinity of NNC2215 is high, thereby contributing to preventing hyperglycaemia. When glucose levels decrease, the switch equilibrates towards a closed state, interfering with the ability of NNC2215 to bind to the insulin receptor, thereby contributing to preventing hypoglycaemia. Insulin backbone, macrocycle, glucoside and glucose models were prepared using BIOVIA Discovery Studio (Dassault Systèmes). b, 3D models of NNC2215 in the open and closed forms. The insulin backbone is shown as ribbons and the switch elements (glucoside and macrocycle) are shown as stick representations. Insulin receptor chains A and C from PDB 6PXV are shown as white and grey surface representations. The open form of NNC2215 (yellow) has free glucose (orange; top left corner) bound to the macrocycle at B29. The B1–glucoside of NNC2215 in the open form is shown in orange (on the right). The closed form of NNC2215 (cyan) has the glucoside bound in the macrocycle and shows a clash between the C-terminal part of the insulin B-chain, including the switch and the C-terminal domain of the insulin receptor (α-CT, purple).
