[A2-Norleucine]Insulin. An Analog with Unanticipated Biological Properties

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Abstract
The simple replacement of the A2-isoleucine by norleucine in the insulin molecule gave an analog [A2-norleucine]insulin ([NleA2]-insulin) which possessed insignificant rat receptor-binding affinity and in vitro biological rat activity, 0.6 and 0.9%, respectively, compared to the natural hormone. Circular dichroic studies showed that this analog is monomeric and indicated that the helical segment A2-A8 and the .beta. strand B24-B29 have undergone conformational changes. The reduced receptor-binding affinity of [NleA2]insulin is attributed to the distortion ofthe A2-A8 helical segment which in turn may lead to the displacement of the A1, A5 and A19 residues which are putatively involved in receptor binding.