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The Design of SCI‐57: An Ultrastable, Rapid‐acting, Single‐chain Insulin Analog

There are approximately 415 million people with Diabetes Mellitus worldwide and there exists a growing need for an ultrastable, heat resistant formulation of rapid‐acting insulin to treat the millions of people who live in developing countries where temperatures routinely exceed 45ºC. The heat resistance and stability of insulin is especially crucial due to the fact that insulin degrades ten times faster for every 10°C increase in temperature above 25°C. Several rapid‐acting insulin analogs have been created, though most do not last longer than 30 days and are reliant on the expensive cold chain delivery system of insulin analogs. This is due to chemical and physical degradation by way of deamidation, transamidation and cross‐beta assembly of linear polymers, or fibrillation. Rapid‐acting analogs must also combat the formation of the inactive hexameric formulation of insulin due to the presence of zinc and an excess of hydrogen ions. A single‐chain insulin analog has been created called SCI‐57 which consists of a glycine rich peptide (6 residues in length) that connects the A and B chains of the insulin analog. Adding a peptide tether will restrict splaying of the A and B chains, thus decreasing the risk of fibrillation even under high temperatures. To ensure that the analog is rapid‐acting and will not form storage hexamers, SCI‐57 has replaced ThrA8 with His to omit an unfavorable beta‐branched amino acid and HisB10 with Asp to create a more favorable relationship with the electrostatic dipole of the B‐chain alpha helix. Replacing HisB10 with Asp also blocks zinc binding, furthermore ensuring that the analog in its active, monomeric state. Both of these actions triple the activity of two‐chain analogs which will also benefit SCI‐57 by allowing it to bind quickly to the insulin receptor. Furthermore, SCI‐57 is much more resistant to fibrillation under high temperatures than previous analogs and maintains insulin receptor affinity as well as efficiency. The Nueva School MSOE Center for Biomolecular Modeling MAPS Team used 3‐D modeling and printing technology to examine structure‐function relationships of SCI‐57.