Low concentration structural dynamics of lanreotide and somatostatin‐14

Abstract

Lanreotide, a synthetic cyclic octapeptide, analogue of the peptide hormone somatostatin-14 (SST-14), is routinely used as a long-acting medication in the management of neuroendocrine tumors. Despite its therapeutic importance, low concentration structural data is still lacking for lanreotide. In fact, the major part of the previous structural investigations were focused on the remarkable aggregation properties of this peptide, appearing at high concentrations (>5 mM). Here, we have applied three optical spectroscopic techniques, i.e. fluorescence, circular dichroism and Raman scattering, for analyzing the structural dynamics at the concentrations below 5 mM, where lanreotide exists either in a monomer state or at the first stages of aggregation. The obtained data from lanreotide were discussed through their comparison with those collected from SST-14, leading us to the following conclusions: (i) The central D-Trp residue, forming with its adjacent Lys the main receptor interacting part of lanreotide, keeps a constant high rotational freedom whatever the environment (water, water/methanol, methanol). (ii) A solvent-dependent tight β-turn, belonging to the type-II' family, is revealed in lanreotide. (iii) Raman data analyzed by band decomposition in the amide (I and III) regions allowed estimation of different secondary structural elements within the millimolar range. Interestingly, the applied protocol shows a perfect agreement between the structural features provided by the amide I and amide III Raman markers.

Disulfide linkage Raman markers: a reconsideration attempt

“…This fact has been emphasized in our recent reports devoted to somatostatin and its cyclic analogs . To give an example, somatostatin, a short size peptide hormone (14 AAs, N S‐S = 1) presents a multicomponent ν (S‐S) Raman profile at low concentrations (≤5 mM), where it adopts a loose turn in aqueous media . Upon increasing concentration, its spectral shape tends toward a monocomponent profile, showing the gradual tightening of its cyclic part caused by aggregation …”

“…We should also remark the multicomponent aspect of the ν (S‐S) spectral region, arising from the inherent structural dynamics of a peptide chain. This fact has been emphasized in our recent reports devoted to somatostatin and its cyclic analogs . To give an example, somatostatin, a short size peptide hormone (14 AAs, N S‐S = 1) presents a multicomponent ν (S‐S) Raman profile at low concentrations (≤5 mM), where it adopts a loose turn in aqueous media .…”

“…GRAMS /32 software (Galactic Industries) was used for buffer subtraction, as well as for curve fitting by means of pseudo‐Voigt (Gaussian + Lorentzian) functions, with the Lorentzian contribution kept equal to or greater than 50%. On the basis of our recent experimental works on a series of disulfide‐containing cyclic peptides, components with a half width (at half height) not exceeding ~15 cm −1 , were used in the band decomposition of the ν (S‐S) spectral region.…”

Anchoring Sites of Fibrillogenic Peptide Hormone Somatostatin-14 on Plasmonic Nanoparticles

“…This feature might obviously facilitate the binding of this peptide to plasmonic NPs covered by negatively charged ions. (ii) Mainly induced by the polar/apolar balance of its amino acid residues, the large size loop of SST-14 was shown to be unstructured at submillimolar concentrations, 18,19 revealing a progressive structuring trend upon increasing concentration over the millimolar range. Especially, in the 20 to 60 mM range SST-14 was shown to form high order self-assemblies, referred to as nanofibrils, spherulites and nanofibers.…”

Disorder-to-Order Markers of a Cyclic Hexapeptide Inspired from the Binding Site of Fertilin β Involved in Fertilization Process

“…16−18 In cyclic peptides, the closure constraint (imposed for instance by a disulfide bond), the length, and the amino acid composition of its closed part were shown to be the key elements in their structural behaviors. 19−21…”