1. A novel synthetic luteinizing hormone-releasing hormone (LHRH) analogue coupled with modified β-cyclodextrin: insight into its intramolecular interactions
- Author
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Golfo G. Kordopati, Theodore Tselios, Thomas Mavromoustakos, Tahsin F. Kellici, Simona Golic Grdadolnik, Franci Merzel, and Gerasimos M. Tsivgoulis
- Subjects
Magnetic Resonance Spectroscopy ,Stereochemistry ,Biophysics ,Molecular Dynamics Simulation ,Biochemistry ,Gonadotropin-Releasing Hormone ,chemistry.chemical_compound ,Drug Delivery Systems ,Humans ,Molecular Biology ,Indole test ,chemistry.chemical_classification ,Binding Sites ,Cyclodextrin ,Molecular Structure ,beta-Cyclodextrins ,Tryptophan ,Rational design ,Nuclear magnetic resonance spectroscopy ,Protein Structure, Tertiary ,PyBOP ,chemistry ,Models, Chemical ,Drug Design ,Drug delivery ,Two-dimensional nuclear magnetic resonance spectroscopy ,Protein Binding - Abstract
Background Cyclodextrins (CDs) in combination with therapeutic proteins and other bioactive compounds have been proposed as candidates that show enhanced chemical and enzymatic stability, better absorption, slower plasma clearance and improved dose–response curves or immunogenicity. As a result, an important number of therapeutic complexes between cyclodextrins and bioactive compounds capable to control several diseases have been developed. Results In this article, the synthesis and the structural study of a conjugate between a luteinizing hormone-releasing hormone (LHRH) analogue, related to the treatment of hormone dependent cancer and fertility, and modified β -cyclodextrin residue are presented. The results show that both the phenyl group of tyrosine (Tyr) as well as the indole group of tryptophan (Trp) can be encapsulated inside the cyclodextrin cavity. Solution NMR experiments provide evidence that these interactions take place intramolecularly and not intermolecularly. Conclusions The study of a LHRH analogue conjugated with modified β -cyclodextrin via high field NMR and MD experiments revealed the existence of intramolecular interactions that could lead to an improved drug delivery. General significance NMR in combination with MD simulation is of great value for a successful rational design of peptide–cyclodextrin conjugates showing stability against enzymatic proteolysis and a better pharmacological profile.
- Published
- 2014