CONTRIBUTION OF THE B16 AND B26 TYROSINE RESIDUES TO THE BIOLOGICAL-ACTIVITY OF INSULIN

We report the synthesis and biological evaluation of five insulin anal ogues in which one or both of the B-chain tyrosine residues have been substituted. [B16 Phe]insulin and [B16 Trp]insulin display a very mode st reduction in potency (c. 65%) relative to porcine insulin; [B26 Phe ]insulin is less active (30-50%), and the doubly substituted [B16 Phe, B26 Phe]insulin displays still lower potency (c. 35%). The further su bstitution of Asp for B10 His in [B16 Phe, B26 Phe]insulin raises its activity to approximately twofold greater than natural insulin, an inc rease of approximately fivefold over the parent compound. We conclude that the bulk and/or aromaticity of the amino acid residue at position B16, but not its hydrogen-bonding capacity, contributes to the biolog ical activity of the hormone. We further conclude that hydrogen-bondin g capacity or special side-chain packing characteristics are required at the B26 position for insulin to display high biological activity.