[Insulin analogues with permuted A chain N-terminus (author's transl)].
By partial synthesis insulin analogues were prepared in which the amino acid in position 1 of the A chain was permuted. Glycine in position A 1 was exchanged for leucine, tert.- butyloxycarbonylvaline, valine, proline, lysine as well as glutamic acid. Two pathways of partial synthesis were followed: Firstly, des-1-glycine-A-chain S-sulfonate was reacted with active esters of tert.-butyloxycarbonylamino acids. The ensuing modified A-chains were combined with natural B-chain to give A1-permuted insulins. In the second procedure, the preparation of tris-Boc-[A1-leucine]insulin was accomplished by reaction of Boc-leucine N-hydroxysuccinimide ester with NalphaB1,NepsilonB29-bis(tert.-butyloxycarbonyl)-des-A1-glycine-insulin. The protected insulin derivative had been prepared by combination of des-glycine-A-chain with Nalpha1,Nepsilon29-bis(tert.-butyloxycarbonyl)-B-chain. The deprotected analogues differed considerably in their CD-spectra from insulin and possessed low in vitro biological activities of 2.5-17%. Crystallization attempts failed. Thus, the introduction of side chains in position A1 distorts the conformation sterically and decreases the biological activity.
D000595:Amino Acid Sequence; D000596:Amino Acids / Q000032:analysis; D002942:Circular Dichroism; D003460:Crystallization; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000276:immunology; D011487:Protein Conformation; D013056:Spectrophotometry, Ultraviolet
D000596:Amino Acids; D007328:Insulin
Insulin-Analoga mit permutiertem N-Terminus der A-Kette