β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide

Cyclodextrin complexation has a potential to modulate the physicochemical properties of peptide drugs. The ability of peptides to form an inclusion complex can be influenced by factors such as size, amino acid sequence of peptide and the size and charge of the cyclodextrin cavity. In this study, the inclusion complexes of cyclic peptide drug lanreotide acetate with two common β-cyclodextrin derivatives, Sulfobutyl ether β-CD (SBEβ-CD) and hydroxypropyl β-CD (HPβ-CD) were investigated. NMR spectroscopy was used to examine the interaction between β-cyclodextrin derivatives and specific residues of lanreotide.

It was observed that the hydrophobic side chain of aromatic residues in the lanreotide sequence can be fit into the cavity of both β-cyclodextrin derivatives. Additionally, NMR revealed a lower diffusion coefficient and higher hydrodynamic radius of complex, indicative of binding to the cavities. Each aromatic residue was individually studied by substituting alanine in lanreotide to measure its association binding with both β-cyclodextrin derivatives. The alanine-substitute study indicated a stronger binding of SBEβ-CD to Lanreotide compared to HPβ-CD.

Docking studies suggested that the 1:1 inclusion complex is more favorable than higher order complexes due to the steric hindrance and size considerations. The docking analysis indicated the stable conformation of all three aromatic side chains with both β-cyclodextrin derivatives, SBEβ-CDand HPβ-CD.

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Materials

Lanreotide acetate and Alanine substituted derivatives of Lanreotide TFA (≥95% purity; Table 1) were purchased from DGpeptides Co. (Hangzhou, China). SBEβ-CD (Captisol®) – Nominal MW=2163 g/mol and Degree of substitution= 6.4 – were obtained from Ligand Pharmaceutical Co. (Lawrence, KS). The HPβ-CD (KLEPTOSE®) – Nominal MW= 1387 g/mol, Degree of substitution= 4.83- was purchased from Roquette Co. (Keokuk, IA).

Negar Jafari, Justin T. Douglas, Sarah A. Neuenswander, Payam Kelich, Michael J. Hageman, β-Cyclodextrin Derivatives Bind Aromatic Side Chains of the Cyclic Peptide Lanreotide, Journal of Pharmaceutical Sciences, 2024, ISSN 0022-3549, https://doi.org/10.1016/j.xphs.2024.10.042.

Read also our introduction article on Binders here: