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Enhanced Cellular Uptake of Antisecretory Peptide AF-16 through Proteoglycan Binding

Maria Matson Dzebo (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Anna Reymer (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Kristina Fant ; Per Lincoln (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Bengt Nordén (Institutionen för kemi- och bioteknik, Fysikalisk kemi) ; Sandra Rocha (Institutionen för kemi- och bioteknik, Fysikalisk kemi)
Biochemistry (0006-2960). Vol. 53 (2014), 41, p. 6566–6573.
[Artikel, refereegranskad vetenskaplig]

Peptide AF-16, which includes the active site of Antisecretory Factor protein, has antisecretory and antiinflammatory properties, making it a potent drug candidate for treatment of secretory and inflammatory diseases such as diarrhea, inflammatory bowel diseases, and intracranial hypertension. Despite remarkable physiological effects and great pharmaceutical need for drug discovery, very little is yet understood about AF-16 mechanism of action. In order to address interaction mechanisms, we investigated the binding of AF-16 to sulfated glycosaminoglycan, heparin, with focus on the effect of pH and ionic strength, and studied the influence of cell-surface proteoglycans on cellular uptake efficiency. Confocal laser scanning microscopy and flow cytometry experiments on wild type and proteoglycan-deficient Chinese hamster ovary cells reveal an endocytotic nature of AF-16 cellular uptake that is, however, less efficient for the cells lacking cell-surface proteoglycans. Isothermal titration calorimetry provides quantitative thermodynamic data and evidence for that the peptide affinity to heparin increases at lower pH and ionic strength. Experimental data, supported by theoretical modeling, of peptide−glycosaminoglycan interaction indicate that it has a large electrostatic contribution, which will be enhanced in diseases accompanied by decreased pH and ionic strength. These observations show that cell-surface proteoglycans are of general and crucial importance for the antisecretory and anti-inflammatory activities of AF-16.

Nyckelord: AF-16, Antisecretory Factor, Peptide, Cellular Uptake, Proteoglycans, Heparin, Isothermal Titration Calorimetry, Confocal Microscopy, Flow Cytometry

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Denna post skapades 2014-11-03. Senast ändrad 2016-07-01.
CPL Pubid: 205209


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Institutionen för kemi- och bioteknik, Fysikalisk kemi (2005-2014)


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Cellular Dyes and Bioactive Peptides - Cell Membrane Interactions and Cellular Uptake