Chemically and Thermodynamically Stable Insulin Analogues and Improved Methods for their Production

A single chain insulin (SCI) compound of the formula:

• Stable B chain-C′-Stable A chain Formula (I)
• having the properties of high affinity for the insulin receptor and low affinity for the IGF-1 receptor with chemical and thermodynamic degradation profiles such that the SCI can be formulated and stored for extended periods of time without refrigeration;
• wherein Stable B chain and Stable A chain are modified human insulin chains;
• and
• wherein C′ covalently links Stable B chain and Stable A chain, and is a peptide of about 5 to 9 amino acids comprising the following sequence:
• Y-P-G-D-X (SEQ ID NO:
• 1);
• wherein X is any amino acid.