Driving Forces in the Delivery of Penetratin Conjugated G Protein Fragment

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• 作者：Stefania Albrizio ; Laura Giusti ; Gerardino D'Errico ; Cinzia Esposito ; Francesca Porchia ; Gabriella Caliendo ; Ettore Novellino ; Maria R. Mazzoni ; Paolo Rovero ; Anna M. D'Ursi
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 5, 2007
• 年：2007
• 卷：50
• 期：7
• 页码：1458 - 1464
• 全文大小：198K
• 年卷期：v.50,no.7(April 5, 2007)
• ISSN：1520-4804

文摘

A42 is a chimera peptide consisting of G_s(374-394)C³⁷⁹A-the 21-mer C terminus of the G_s protein, ableof adenosine inhibitory activity-and penetratin-the 16 residue fragment, derived from the homeodomainof the Drosophila transcription factor Antennapedia. A42 is able to cross cell membranes and to inhibit A_2Aand A_2B adenosine and -adrenergic receptor stimulated camps (D'Ursi et al. Mol. Pharmacol. 2006, 69,727-36). Here we present an extensive biophysical study of A42 in different membrane mimetics, with theobjective to evaluate the molecular mechanisms which promote the membrane permeation. Fluorescence,CD, and NMR data were acquired in the presence of negatively charged and zwitterionic sodium dodecylsulfate and dodecylphosphocholine surfactants. To validate the spectroscopic results in a larger scale,fluorescence microscopy experiments were performed on negatively charged and zwitterionic dipalmitoylphosphatidylglycerol and dipalmitoylphosphatidylcholine vesicles. Our results show that the internalizationof A42 is mainly driven by electrostatic interactions, hydrophobic interactions playing only a secondary,sinergistic role. The distribution of the charges along the molecule has an important role, highlighting thatinternalization is a process which requires a specific matching of peptide and membrane properties.