Synthetic glycopeptide substrates for receptor-mediated endocytosis by macrophages.

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Abstract
Mammalian macrophages contain a transport system that binds and internalizes glycoproteins with exposed mannose residues. This system and analogous systems on other types of cells require substrates to bear multiple nonreducing terminal residues of the appropriate sugar for effective uptake. Small multivalent synthetic glycopeptides with mannose residues covalently linked through a spacer arm to the .alpha.- and .epsilon.-amino groups of lysine, dilysine and trilysine are competitive inhibitors of rat alveolar macrophage uptake of the neoglycoprotein mannosyl-bovine serum albumin with inhibition constants in the .mu.M range. Various compounds could be covalently attached to the .alpha.-carboxyl group of these glycopeptides with substantial retention of inhibitory potency. This uptake system does not recognize galactose residues and the galactosyl analog of an inhibitory mannosylpeptide did not inhibit uptake of mannosyl-bovine serum albumin. The trimannosyldilysine ligand is not only an inhibitor but also a substrate for specific uptake by macrophages, as shown with an 125I-labeled derivative. Macrophages bound 6.4 .times. 105 molecules/cell at 0.degree. C with a Kd of 2 .mu.M. At 21.degree. C the cells could internalize the labeled conjugate with an apparent Km of 6 .mu.M and a Vmax of 1.7 .times. 105 molecules/min per cell. The Kd and Vmax are similar to the inhibition constant of 9 .mu.M determined at 21.degree. C for inhibition by this conjugate of mannosyl-bovine serum albumin uptake. These synthetic substrates may be useful in targeting pharmacologic agents to macrophages and analogous compounds may target such agents to other types of cell.

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