Development of neo-biologics targeted on protein-protein interaction sites

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To develop novel therapeutics for human deficiencies (lysosomal storage diseases) of lysosomal cathepsin A (CathA) and neuraminidase-1 (NEU1) based on protein-protein interaction between CathA and NEU1, we produced transgenic (Tg) silkworm strains overexpressing human CathA and NEU1 in middle silk glands, and succeeded in purification and elucidation of X-ray crystal structure of the enzymatically active CathA. The conjugates of active CathA purified from Tg silk glands and cell-penetrating peptides (R8) had replacement effects on cultured fibroblasts derived from patients with CathA deficiency (Galactosialidosis) to reduce the accumulated sialyloligosaccharides. In addition, siastatin B was found to have stabilizing effects like a chaperone compound on recombinant human cytosolic NEU2 with structural similarity to NEU1.