Membrane dipeptidase is the receptor for a lung-targeting peptide identified by in vivo phage display.
In vivo phage display is a powerful method to study organ- and tissue-specific vascular addresses. Using this approach, peptides capable of tissue-specific homing can be identified by performing a selection for that trait in vivo. We recently showed that the CGFECVRQCPERC (termed GFE-1) peptide can selectively bind to mouse lung vasculature after an intravenous injection. Our aim in the present study was to identify the receptor for this lung-homing peptide. By using affinity chromatography, we isolated a 55-kDa lung cell-surface protein that selectively binds to the GFE-1 peptide. Protein sequencing established the identity of the receptor as membrane dipeptidase (MDP), a cell-surface zinc metalloprotease involved in the metabolism of glutathione, leukotriene D4, and certain beta-lactam antibiotics. Phage particles displaying the GFE-1 peptide selectively bind to COS-1 cells transfected with the murine MDP cDNA. Moreover, the synthetic GFE-1 peptide could inhibit MDP activity. By establishing MDP as the receptor for the GFE-1 peptide, our results suggest potential applications for both MDP and the GFE-1 peptide in delivery of compounds to the lungs. This work also demonstrates that cell-surface proteases can be involved in tissue-specific homing.
Rajotte
D
D
Cancer Research Center, The Burnham Institute, La Jolla, California 92037, USA.
Ruoslahti
E
E
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D019556:COS Cells; D018076:DNA, Complementary; D004150:Dipeptidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D014162:Transfection
D018076:DNA, Complementary; C118896:GFE-1 peptide; D009842:Oligopeptides; D004150:Dipeptidases; C038937:dipeptidase