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

Area of Science:

• Biochemistry
• Pharmaceutical Chemistry
• Structural Biology

Background:

• Zinc stabilizes insulin hexamers for long-acting preparations.
• Dizinc insulin crystal structure reveals a central cavity within the hexamer.
• This cavity can potentially accommodate small organic molecules for enhanced stabilization.

Purpose of the Study:

• To design and synthesize molecules that further stabilize the insulin hexamer by binding to the central cavity.
• To investigate a novel binding mechanism for stabilizing insulin hexamers.

Main Methods:

• Utilized computer graphic techniques to design potential stabilizing molecules.
• Synthesized benzene-1,4-disulfonic acid, a designed compound.
• Employed weight-average molecular weight measurements to assess insulin stability in solution.
• Conducted control experiments with related structures.

Main Results:

• Benzene-1,4-disulfonic acid significantly increased the weight-average molecular weight of insulin in solution.
• Control experiments supported the proposed binding mechanism for stabilization.
• The designed molecule demonstrated effective stabilization of insulin hexamers.

Conclusions:

• It is possible to design molecules that bind within the dizinc insulin hexamer cavity.
• Benzene-1,4-disulfonic acid effectively stabilizes insulin hexamers through a specific binding mechanism.
• This approach offers a strategy for developing more stable long-acting insulin formulations.