Conformationally constrained peptide analogs with hypoglycaemic activity

Chirality of Biomolecules and Biotechnology Products

“…The α-aminosuccinimide (Asu11) octapeptide analog of human growth hormone hGH [6][7][8][9][10][11][12][13] (Leu6-Ser-Arg-Leu-Phe-Asu-Asn-Ala13) has been reported to have hypoglycemic activity, while the corresponding peptide with Asp at position 11 is inactive [47]. To determine whether this change in activity is caused by conformational and/or stereoelectronic effects, the incorporation of two different isomeric γ-lactam structures at position 11 has been investigated.…”

Formation of an RNase A derivative containing an aminosuccinyl residue in place of asparagine 67

“…It has been shown that in a peptide chain the Asu residue promotes the folding of the chain to a II′ β‐turn,16 with the Asu residue in the second position of the turn. This folded conformation has been shown to cause the hypoglycemic activity of some Asu peptides 17. By contrast, only few proteins with an Asu residue have been isolated so far 18–20…”

Synthesis of ?-aminosuccinimide-containing peptides in Fmoc-based SPPS

“…In previous reports from this laboratory, the synthesis, characterisation and in vitro and in vivo biological activities of hypoglycaemic c~-aminosuccinimide-containing variants of human growth hormone [6][7][8][9][10][11][12][13], Asu~-hGH [6 -13] amide (1; see Scheme 1), and its ~'-lactam analogues have been described [1][2][3]. The Asu ll-hGH [6][7][8][9][10][11][12][13] amide peptide was first discovered as a byproduct during the t-Boc-based solid-phase peptide synthesis of Lo~-aspartyl-containing hGH [6][7][8][9][10][11][12][13] under conditions of base catalysis during neutralisation steps [1,4].…”

“…The Asu ll-hGH [6][7][8][9][10][11][12][13] amide peptide was first discovered as a byproduct during the t-Boc-based solid-phase peptide synthesis of Lo~-aspartyl-containing hGH [6][7][8][9][10][11][12][13] under conditions of base catalysis during neutralisation steps [1,4]. Our subsequent studies have sought to optimise the conditions for this o~-aminosuccinimide (Asu) formation and have included increasing the time of exposure of the resin to tertiary amines, as well as the use of trifluoromethane sulfonic acid (TFSMA) as the cleavage reagent [2,5]. These measures have been successful, i.e., ~-aminosuccinimide formation can be made to occur exclusively, with none of the L-~-aspartyl-containing peptide detected after cleavage (Table 1).…”