Insulin analogues with modifications in the beta-turn of the B-chain.
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.
Wang
S H
SH
Department of Biochemistry, Mount Sinai School of Medicine, City University of New York, New York 10029-6574.
Hu
S Q
SQ
Burke
G T
GT
Katsoyannis
P G
PG
D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002417:Cattle; D002462:Cell Membrane / Q000378:metabolism; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008055:Lipids / Q000096:biosynthesis; D008099:Liver / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D013329:Structure-Activity Relationship
D007328:Insulin; D008055:Lipids; C071138:insulin, Aib(21) B-chain-; C071139:insulin, Aib(22) B-chain-; C071137:insulin, Glu(21) B-chain-; D011972:Receptor, Insulin