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The effect of palmitoylation on the conformation and physical stability of a model peptide hormone

DOI: 10.1016/j.ijpharm.2014.06.008 DOI Help
PMID: 24928136 PMID Help

Authors: Edoardo Longo (Diamond Light Source) , Emiliana De Santis (Medway School of Pharmacy, Diamond Light Source) , Rohanah Hussain (Diamond Light Source) , Chris Van Der Walle (MedImmune Ltd., Formulation Sciences, Granta Park, Cambridge) , Jose Casas-finet (MedImmune LLC, Analytical Biochemistry, Gaithersburg) , Shahid Uddin (MedImmune Ltd., Formulation Sciences, Granta Park, Cambridge) , Ana Dos Santos (MedImmune Ltd., Formulation Sciences, Granta Park, Cambridge) , Giuliano Siligardi (Diamond Light Source)
Co-authored by industrial partner: Yes

Type: Journal Paper
Journal: International Journal Of Pharmaceutics , VOL 472 , PAGES 156 - 164

State: Published (Approved)
Published: September 2014
Diamond Proposal Number(s): 7559 , 8082

Abstract: Peptides are ideal drug candidates due to their potency and specificity, but suffer from a short half-life and low membrane permeability. Acylation can overcome these limitations but the consequences to stability under different formulation conditions and stresses are largely unreported. Using synchrotron radiation circular dichroism (SRCD), we show that palmitoylation of a 28 amino acid peptide hormone (pI 9.82) induced a structural transition from 310-helix to α-helix, irrespective of buffer type and pH investigated (5.5–8.0) when compared to the non acylated analogues. These conformational preferences were retained in the presence of non-ionic micelles but not anionic micelles, which induced an α-helical structure for all peptides. Palmitoylation promoted an irreversible peptide denaturation under thermal stress at pH ≥ 6.5 and increased the propensity for loss of helical structure under high photon flux (here used as a novel accelerated photostability test). The presence of either ionic or non-ionic micelles did not recover these conformational changes over the same irradiation period. These results demonstrate that acylation can change peptide conformation and decrease thermal-/photo-stability, with important consequences for drug-development strategies.

Journal Keywords: Vasoactive Intestinal Peptide; Circular Dichroism; Photo-Degradation; Conformation; Accelerated Stability Studies; Drug Development

Subject Areas: Medicine, Technique Development, Chemistry


Instruments: B23-Circular Dichroism