Günter Bovermann

A 1H-NMR study of the solution conformation of secretin Resonance assignment and secondary structure

The solution conformation of the 27 residue polypeptide hormone secretin has been investigated by 1H‐NMR spectroscopy under conditions where it adopts a fully ordered structure as judged by circular dichroism spectroscopy, namely in an aqueous solution of 40% (v/v) trifluoroethanol. Using a combination of two‐dimensional NMR techniques the 1H‐NMR spectrum of secretin is completely assigned and its secondary structure is determined from a qualitative interpretation of the nuclear Overhauser enhancement data. It is shown that under these conditions secretin adopts a conformation consisting of an N‐terminal irregular strand (residues 1–6) followed by two helices (residues 7–13 and 17–25) connected by a ‘half‐turn’ (residues 14–16); the last two residues (26 and 27) are again irregular. This conformation is shown to be very similar to that of glucagon in perdeuterated dodecylphosphocholine micelles and to that of the active 1–29 fragment of growth hormone releasing factor in 30% (v/v) trifluoroethanol.

The 3D structure of a cyclosporin analogue in water is nearly identical to the cyclophilin-bound cyclosporin conformation

The conformation of [d‐MeSer3‐d‐Ser‐(O‐Gly8]CS, a water soluble cyclosporin derivative, has been determined in (D6)DMSO and in water using NMR. In these polar solvents the conformation is identical and very similar to the structure found in the cyclophilin‐cyclosporin complex. However, it differs significantly from its conformation in deuterated chloroform. This demonstrates unambiguously that the large structure change is induced primarily by the polar solvent rather than by complex formation with cyclophilin.

The Superior Therapeutic Properties of SOM230 Originate from Unique Structural Elements

A rational drug design approach involving transposition of functional groups from SRIF into a reduced size cyclohexapeptide template has led to the discovery of SOM230, a novel, stable cyclohexapeptide somatostatin mimic which exhibits unique high affinity binding to human somatostatin receptors (sst1-5). SOM230 has potent, long lasting inhibitory effects on growth hormone and insulin-like growth factor-1 release and is a promising development candidate currently under evaluation in phase II clinical trials.