Synthesis, and functional properties of a modified human insulin A-Chain: implication in a ‘Mini-Insulin’ structure determination Original Research Article

The design and total synthesis of a novel insulin A-chain mutant, analogue 3, is reported. In this compound, the cysteines implied in the two insulin inter-chain disulfide bridges are replaced by two serines (residues SerA7 and SerA20) and the intra-A-chain disulfide bridge (residues CysA6 and CysA11) is conserved. This A-chain analogue (3) has been tested in three in vitro cell culture assays, using insulin as a reference. The data clearly showed that analogue 3 mimics insulin effects on DNA synthesis, glucose uptake and glycogen synthesis without loss of potency as compared to insulin. To our knowledge, these are the first results showing that an isolated insulin chain displays functional properties similar to those of insulin. The implication of these new findings in insulin structure–function relationships and in a ‘mini-insulin’ structure determination is discussed.