Possible involvement of the A20-A21 peptide bond in the expression of the biological activity of insulin. 3. [21-Desasparagine,20-cysteine ethylamide-A]insulin and [21-desasparagine,20-cysteine 2,2,2-trifluoroethylamide-A]insulin.
We have synthesized [21-desasparagine,20-cysteine ethylamide-A]insulin and [21-desasparagine,20-cysteine 2,2,2-trifluoroethylamide-A]insulin, which differ from natural insulin in that the C-terminal amino residue of the A chain, asparagine, has been removed and the resulting free carboxyl group of the A20 cysteine residue has been converted to an ethylamide and a trifluoroethylamide group, respectively. [21-Desasparagine,20-cysteine ethylamide-A]insulin displayed equivalent potency in receptor binding and biological activity, ca. 12% and ca. 14%, respectively, relative to bovine insulin. In contrast, [21-desasparagine,20-cysteine 2,2,2-trifluoroethylamide-A]insulin displayed a divergence in these properties, ca. 13% in receptor binding and ca. 6% in biological activity. This disparity is ascribed to a difference in the electronic state of the A20-A21 amide bond in these two analogues. A model is proposed to account for the observation of divergence between receptor binding and biological activity in a number of synthetic insulin analogues and naturally occurring insulins. In this model, changes in the electronic state and/or the orientation of the A20-A21 amide bond can modulate biological activity independently of receptor binding affinity. The A20-A21 amide bond is thus considered as an important element in the "message region" of insulin.
Chu
Y C
YC
Department of Biochemistry, Mount Sinai School of Medicine of the City University of New York, New York 10029.
Wang
R Y
RY
Burke
G T
GT
Chanley
J D
JD
Katsoyannis
P G
PG
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D007202:Indicators and Reagents; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D012756:Sheep; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D007328:Insulin; C054835:insulin, des-Asn(21)-Cys(20)-2,2,2-trifluoroethylamide(A)-; C054834:insulin, des-Asn(21)-Cys(20)-ethylamide(A)-; D011972:Receptor, Insulin