Structure-activity relationship of covalently dimerized insulin derivatives: correlation of partial agonist efficacy with cross-linkage at lysine B29.

Autor: Deppe, C., Breiner, M., Brandenburg, D., Joost, H.
Zdroj: Naunyn-Schmiedeberg's Archives of Pharmacology; 1994, Vol. 350 Issue 2, p213-217, 5p
Abstrakt: The effects of 7 covalently dimerized insulin derivatives on glucose transport in differentiated 3T3-L1 cells were investigated. Symmetric cross-linkage at lysine B29 with a bridge of 2 (oxalyl), 8 (suberoyl) or 12 (dodecanedioyl) carbon atoms produced derivatives with essentially unaltered receptor binding affinity but largely reduced intrinsic activity. Regardless of the chain length, these derivatives inhibited the effect of submaximal insulin concentrations. Insulin derivatives cross-linked at phenylalanine 131 or asymmetrically at 131/1129 were full agonists of the insulin receptor. When lysine B29 was cross-linked with the inactive desoctapeptide(B23-B30)insulin at phenylalanine B1, the intrinsic activity of the resulting dimer was lower than that of insulin, but higher than that of the symmetric B29-dimers. It is concluded that linkage at the B29-lysines, and not at the B1-phenylalanine, leads to partial agonism of dimerized insulin derivatives, regardless of the length of the crosslinker. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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