The device of new hepatotrophic
prodrugs of the
antiviral nucleoside 9-(2-phosphonylmethoxyethyl)adenine (PMEA) with specificity for the
asialoglycoprotein receptor on parenchymal liver cells is described. PMEA was conjugated to bi- and trivalent cluster
glycosides (K(GN)(2) and K(2)(GN)(3), respectively) with nanomolar affinity for the
asialoglycoprotein receptor. The liver uptake of the PMEA
prodrugs was more than 10-fold higher than that of the parent
drug (52+/-6% and 62+/-3% vs. 4.8+/-0.7% of the injected dose for PMEA) and could be attributed for 90% to parenchymal cells. Accumulation of the PMEA
prodrugs in extrahepatic tissue (e.g., kidney, skin) was substantially reduced. The ratio of parenchymal liver cell-to-kidney uptake-a measure of the
prodrugs therapeutic window-was increased from 0.058 +/- 0.01 for PMEA to 1.86 +/- 0.57 for K(GN)(2)-PMEA and even 2.69 +/- 0.24 for K(2)(GN)(3)-PMEA. Apparently both
glycosides have a similar capacity to redirect (
antiviral) drugs to the liver. After cellular uptake, both PMEA
prodrugs were converted into the parent
drug, PMEA, during acidification of the lysosomal milieu (t(1/2) approximately 100 min), and the released PMEA was rapidly translocated into the cytosol. The
antiviral activity of the
prodrugs in vitro was dramatically enhanced as compared to the parent
drug (5- and 52-fold for K(GN)(2)-PMEA and K(2)(GN)(3)-PMEA, respectively). Given the 15-fold enhanced liver uptake of the
prodrugs, we anticipate that the potency in vivo will be similarly increased. We conclude that PMEA
prodrugs have been developed with greatly improved pharmacokinetics and therapeutic activity against
viral infections that implicate the liver parenchyma (e.g., HBV). In addition, the significance of the above
prodrug concept also extends to drugs that intervene in other liver disorders such as
cholestasis and
dyslipidemia.