Insulin analogues containing glucose-controlled conformational switches

摘要

SOLUTION: A two-chain insulin analogue has (i) an A chain modified with a monomeric glucose binding element at or near its N-terminus, and (ii) this bond can be replaced by glucose. It includes a B chain modified at or near its C-terminus by an element reversibly linked to a monomeric glucose binding element. The monomeric glucose binding element may be a (selectively halogenated) phenylboronic acid derivative. The B chain may be modified with a diol-containing element derived from a monosaccharide, disaccharide, or oligosaccharide, a non-saccharide diol-containing structure, or an α-hydroxycarboxylic acid-containing structure. The analog can be prepared by trypsin-mediated semi-synthesis. The formulation is dissolved in a soluble solution at pH 7.0-8.0 in the presence or absence of zinc ions at a molar ratio of 0.0-3.0 per insulin analog monomer, U-10-U The strength can be -1000. A diabetic patient can be administered a physiologically effective amount of the insulin analog subcutaneously, intraperitoneally, or orally. [Selection] Figure 3A