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-speci fic vascular addresses. Using this approach, peptides capable of tissue-spe cific 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-hom ing peptide. By using affinity chromatography, we isolated a 55-kDa lung ce ll-surface protein that selectively binds to the GFE-1 peptide. Protein seq uencing established the identity of the receptor as membrane dipeptidase (M DP), a cell-surface zinc metalloprotease involved in the metabolism of glut athione, leukotriene D-4, and certain beta-lactam antibiotics. Phage partic les displaying the GFE-1 peptide selectively bind to COS-1 cells transfecte d with the murine MDP cDNA. Moreover, the synthetic GFE-1 peptide could inh ibit MDP activity. By establishing MDP as the receptor for the GFE-1 peptid e, our results suggest potential applications for both MDP and the GFE-1 pe ptide in delivery of compounds to the lungs. This work also demonstrates th at cell-surface proteases can be involved in tissue-specific homing.