Insulin - structure, function, design

Successful treatment of diabetic patients with insulin took place over 30 years without knowing the chemical structure of the hort-none. Based on the primary structure and the three-dimensional architecture of the molecule, the highly developed methods of peptide synthesis, protein semisynthesis and biosynthesis via genetical engineering have given access to a large variety of insulin analogues and derivatives with predetermined alterations of the native structure. Bioassays, in combination with continuously refined physical structural analyses, have already given an impressive picture of the importance of many individual amino acid building blocks with respect to receptor binding, stability and dynamics. On this basis strategies could be founded aiming at molecular optimization for diabetes therapy. Analogues with fast and slow action could be designed through molecular modification in areas which are important for physical-chemical behaviour, but are biologically not affected. To this end principles like charge repulsion, sterical hindrance, change of isoelectric point, binding to endogeneous proteins, or crystal contact engineering could successfully be employed.