Fig. 2.

Rational drug design of PCs for lysosomal enzymes. (A) Structural homology of DGJ and GL-3. The iminosugar DGJ has a high level of structural homology with the terminal galactose of GL-3, the natural substrate of α-galactosidase (α-Gal A) that is deficient in Fabry disease. Based upon this homology, it was hypothesized that DGJ could bind to the active site of α-Gal A and act as a PC.⁴⁰ For DGJ and related iminosugars, the nitrogen atom of the piperdine is analogous to the oxygen atom of galactose. The β-4-epi-valienamine carbasugars have also shown activity against α-galactosidases; however, this activity, as well as selectivity over other lysosomal enzymes, is generally poor, with higher activity toward β-galactosidases and β-glucosidases seen with increasing chain length (i.e., R>C₈).¹⁵⁹ (B) Structural homology of isofagomine (IFG) and glucosylceramide (GlcCer). The azasugar IFG is a mimic of GlcCer, the natural substrate of acid β-glucosidase (GCase) that is deficient in Gaucher disease. It has been proposed that the azasugar core of IFG (with the nitrogen atom replacing the anomeric carbon rather the oxygen) is responsible for the β selectivity of this compound, based on the geometries of transition states for the two possible glycosidic bond cleavages.¹⁶⁰ Similarly, the carbasugar N-octyl valienamine (R=C₈H₁₇) acts as a PC for GCase.¹⁶¹ (C) Structural homology of 1-deoxynojirimycin (DNJ) and glycogen. Acid α-glucosidase (GAA), the enzyme that is deficient in Pompe disease, cleaves the α1–4, and to a lesser extent α1–6, glycosidic bonds of lysosomal glycogen to release glucose. The iminosugar DNJ contains a piperdine ring with an array of hydroxyl groups that closely resembles the terminal glucose unit of glycogen. This high level of structural similarity allows DNJ to bind and stabilize GAA. As with other iminosugars, the α- versus β-glucosidase activity of DNJ is based on a transition state mimetic in which the nitrogen atom is analogous to the oxygen atom of glucose.