Design, synthesis, and testing of insulin hexamer-stabilizing agents.

The addition of zinc to insulin solution leads to a long-acting insulin preparation because the zinc stabilizes the less soluble hexameric form of the hormone. It is clear from the crystal structure of dizinc insulin that there is a space at the center of the hexamer, between the two zinc atoms, that could accommodate a small organic molecule. It should thus be possible to design a structure that could further stabilize the insulin hexamer by binding at this site. Computer graphic techniques have been used to design several molecules capable of forming multiple bonds to the six histidine residues surrounding the site. Synthesis and testing of one of these compounds, benzene-1,4-disulfonic acid, show a significant increase in weight-average molecular weight of insulin in solution, and control experiments with related structures suggest that this effect is due to the proposed binding mechanism.