Site 2 single-chain insulin analogues

Abstract

A single-chain insulin analogues may comprise an insulin B-chain polypeptide sequence connected by a connecting polypeptide (or C-domain) sequence to an insulin A-chain polypeptide sequence. The connecting polypeptide sequence may be Glu-Xaa-Gly-Pro-Arg-Arg where Xaa is Glu or Ala. The insulin analogues may additionally comprise Glu or His substitutions at the position corresponding to A8 of human insulin and / or a Glu substitution at the position corresponding to A14 of human insulin. In some embodiments, the insulin analogues may additionally comprise either a Pro or Glu at the positions corresponding to B28 and B29 of wild-type insulin. Additional substitutions may comprise Phe or Trp at the position corresponding to A13 of wild type insulin and / or Gln, Arg, Phe, or Glu at the position corresponding to A17 of wild type insulin. In some embodiments, a Glu substitution at the position corresponding to B16 of wild type insulin may be present. In other embodiments, a Cys substitution may be present at the positions corresponding to A10 and / or B4 of wild-type insulin. In addition or in the alternative, the analogue may comprise a His or Ala substitution at the position corresponding to B22 of wild-type insulin and / or the connecting polypeptide sequence may be Glu-Glu-Gly-Pro-Ala-His. A method of treating a patient with diabetes mellitus comprises administering a physiologically effective amount of the insulin analogue or a physiologically acceptable salt thereof to a patient by means of intravenous, intraperitoneal, or subcutaneous injection.

Description

[0001] Statement Regarding Federally Funded Research or Development [0002] This invention was made with government support under Grant Numbers DK040949 and DK074176 awarded by the National Institutes of Health. The US Government has certain rights in this invention. [0003] Background of the invention [0004] The present invention relates to polypeptide hormone analogs which exhibit enhanced pharmaceutical properties, such as altered pharmacokinetic and pharmacodynamic properties, ie conferring a shortened duration of action relative to soluble formulations of the corresponding wild-type human hormone. More particularly, the present invention relates to single chain insulin analogues which exhibit such properties. Even more particularly, the present invention relates to insulin analogs comprising (i) one or more of One or more B-chain substitutions known in the art to accelerate the absorption of insulin analogues from subcutaneous depots into the bloodstream. The insuli...

AI Technical Summary

Problems solved by technology

Therefore, it is expected that modifications or substitutions generally in the insulin molecule that introduce modest perturbations of IR binding (as assessed in vitro) will be well tolerated in vivo and, in terms of potency or (in the absence of an effect on self-assembly ) other pharmacological properties are indistinguishable from wild-type insulin—or even as in 2-F-Phe B24 -DKP-Insulin is more potent and prolonged in the case of

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