Tuftsin is an immunostimulatory tetrapeptide (TKPR) that binds to specific receptors on the surface of macrophages and polymorphonuclear leukocytes, stimulating their migration, phagocytic, bactericidal, and tumoricidal activity. Soon after its discovery, a pentapeptide tuftsin analog (TKPPR) was synthesized as an antagonist of tuftsin receptors to bind 20-fold stronger than tuftsin. Since enhanced affinity can be achieved by multivalent binding of ligands, a tetrameric TKPPR was recently reported with 45-fold stronger binding than TKPPR.Aminopterin (AMT) is an antineoplastic drug with immunosuppressive properties. Attaching AMT to target-specific ligands may improve the efficacy of the drug through increased selectivity and reduced toxicity.Here we report the design and synthesis of the first tetra-tuftsin aminopterin conjugate for treating inflammation. TKPPR was prepared by solution phase synthesis. After connecting the TKPPR subunits to the iminodipropionic acid-based symmetric central core, the intermediate was attached to AMT via a disulfide-based cleavable linker to afford the final conjugate (1 ).

Design and synthesis of the first tetrameric tuftsin aminopterin conjugate for active targeting therapy of autoimmune diseases

248th National Meeting (2014)

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