Human insulin analogs and preparations containing them

Details Human insulin analogs and preparations containing them Human insulin analogs and preparations containing them

1991-03-19

1992-09-22

Cashion, Jr., Merrell C.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Insulin; related peptides

A61K 3726, A61K 3702

Patent

active

051497778

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to novel human insulin analogs exhibiting a high specific biological activity as well as insulin preparations containing the human insulin analogs of the invention.


BACKGROUND ART

Ever since the discovery of insulin in 1922 many different types of insulin preparations have been used for the treatment of Diabetes mellitus. At the beginning exclusively insulin solutions exhibiting a rapidly commencing and relatively rapidly ceasing insulin activity were used, but later on insulin preparations exhibiting a wider profile of activity procured by lowering of the solubility of insulin by means of additions as e.g. zinc salt and/or protamines have been produced. For reasons of availability the insulin used herefor has normally been recovered from Pancreas from domestic animals, most frequently oxes, pigs and sheep, however, recently preparations containing human insulin of biotechnological origin have also appeared on the market.
Throughout the years a large number of artificially prepared analogs of human insulin has been described, usually with the purpose of elucidating the influence of the structure on the activity, vide e.g. Marke et al., Hoppe-Seyler's Z. Physiol. Chem. 360, p. 1619-32 (1979). Investigations of the activity of substitutions of the (B22-B26)-sequence of the insulin on the receptor binding have been of particular interest, as said sequence is considered to be the main field of binding for the insulin receptor, and as naturally occurring mutations have been found with substitutions in said field. Vide e.g. S. Shoelson et al. PNAS 80, p. 7390-94 (1983) and M. Kobayashi et al.: Biomed. Res. 5 (3) p. 267-72 (1984). Very low activities for analogs in which Phe(B24) or Phe(B25) are replaced are thus found here, and therefore it is concluded that the presence of these two amino acids is of decisive importance to the receptor binding.
Replacements in the insulin molecule can also be introduced with the purpose of improving the profile of activity of the insulin in the treatment of Diabetes. Thus, e.g. Danish Patent Application No. 5457/86 discloses that one or more replacements of Glu in the insulin molecule by a neutral amino acid residue causes a shifting of the zone of precipitation of the insulin in such a way that a slow release after injection is obtained.
Moreover, Danish Patent Application No. 4116/86 discloses insulin analogs being particularly rapidly absorbed after injection. This effect is a result of the fact that by means of hydrophilic replacements in particular in the B9and in the B28-positions in the insulin molecule a suppression of the aggregation ability of the insulin is obtained so that it is essentially present as monomer. However, a number of these insulin analogs exhibits a reduced biological activity.
Peptides 1980, Proceedings of the Sixteenth European Peptide Symposium Helsingor, Denmark, Aug. 31-Sep. 6, 1980, p. 372-377 describes the preparation of [Tyr.sup.B25, Ala.sup.B30 ]-human insulin by enzymatic coupling of the corresponding protected octapeptide to des-octapeptide (B23-B30) insulin followed by deprotection with trifluoroacetic acid. No data of biological activity is stated.
Biol. Chem. Hoppe-Seyler 1987, 368(6), p. 709-716 describes the preparation of analogs of des-(B26-B30)- insulin-B25-amide in which Phe.sup.B25 is replaced by Tyr.sup.B25 or His.sup.B25 thereby obtaining an increased activity of 230 and 370%, respectively. The analogs are truncated and at the B25 position.


DISCLOSURES OF THE INVENTION

It has now surprisingly been found that certain human insulin analogs in which Phe in position B25 is replaced by His or Tyr and optionally further one or more of the amino acid residues in positions A4, A8, A17, A21, B9, B10, B12, B13, B21, B26, B27, B28, and B30 is replaced by another amino acid residue, and in which the amino acid residue in position B30 moreover may be missing totally or be blocked at the C-terminal in the form of ester or amide, exhibit a higher biological activity than in such case where Ph

REFERENCES:
Casaretto et al, Biol. Chem. Hoppe Seyler vol. 368 709-716 Jun., 1981.
Fischer et al, Biol. Chem. Hoppe Seyler vol. 366 521-515 May, 1985.
Peptides 1980, Proc. of the 16th European Peptide Symposium Helsingor, Denmark Aug. 31-Sep. 6, 1980 372-377.

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