Acyclovir–Glycoprotein conjugates are potent inhibitors of hepatitis B virus replication

AbstractReceptor-mediated targeting to the liver using galactose-terminated ligands is a promising strategy for site-specific delivery of antiviral drugs for treatment of hepatitis B virus infection. Optimization of drug conjugates for receptor-mediated delivery depends, in part, on judicious selection of coupling chemistry between drug and receptor-specific ligand. We synthesized three chemically distinct conjugates: acyclovir linked through a γ-aminobutyryl ester to asialoorosomucoid; acyclovir linked through a succinyl ester to polylysine-asialoorosomucoid; and acyclovir linked to polylysine-asialoorosomucoid through a monophosphoryl linkage (ACV-MP-PL-ASOR). All conjugates were rapidly cleared by the liver when tail-vein injected in mice. The conjugates inhibited replication of hepatitis B virus (HBV) DNA in cultured cells at concentrations that were dependent on the structure of the cross-linker and the extent of modification that the protein endured during coupling with drug. ACV-MP-PL-ASOR displaye...

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