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  • Title: Insulin analogues with modifications in the beta-turn of the B-chain.
    Author: Wang SH, Hu SQ, Burke GT, Katsoyannis PG.
    Journal: J Protein Chem; 1991 Jun; 10(3):313-24. PubMed ID: 1910463.
    Abstract:
    The beta-turn formed by the amino acid residues 20-23 of the B-chain of insulin has been implicated as an important structural feature of the molecule. In other biologically active peptides, stabilization of beta-turns has resulted in increases in activity. We have synthesized three insulin analogues containing modifications which would be expected to increase the stability of the beta-turn. In two analogues, we have substituted alpha-aminoisobutyric acid (Aib) for the Glu residue normally present in position B21 or for the Arg residue normally present in position B22; in a third compound, we have replaced the Glu residue with its D-isomer. Biological evaluation of these compounds showed that [B21 Aib]insulin displays a potency ca. one-fourth that of natural insulin, while [B22 Aib]insulin is less than 10% as potent. In contrast, [B21 D-Glu]insulin is equipotent with natural insulin. We conclude that the beta-turn region of the insulin molecule normally possesses considerable flexibility, which may be necessary for it to assume a conformation commensurate with high biological activity. If this is the case, [B21 D-Glu]insulin may exhibit a stabilized geometry similar to that of natural insulin when bound to the insulin receptor.
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