Renal Targeting of Arginine-Vasopressin by Modification with Carbohydrates at the Tyrosine Side Chain.

Abstract

To extend the utility of a renal targeting system using carbohydrate derivatives, we investigated the in vivo tissue distribution in rats of arginine-vasopressin (AVP) derivatives modified at the phenolic hydroxy group of tyrosine by linking it to some sugars, namely D-glucose, D-galactose, D-mannose and L-fucose, via an octamethylene group. The glycosyl and mannosyl derivatives of AVP exhibit renal-selective distribution in vivo. In addition, the glucosyl and mannosyl derivatives exhibited specific binding to the kidney microsomal fraction in vitro. Modification with D-glucose or D-mannose at the tyrosine side chain is a suitable methodology for renal targeting, as well as at N-terminal amine.

Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides

“…We, along with others, have hypothesized that glycosylation of smaller peptides may have desirable effects on the pharmacokinetic and/or pharmacodynamic properties of the parent peptide (Albert et al, 1993;Polt et al, 1994;Negri et al, 1998;Susaki et al, 1999;Suzuki et al, 1999a,b;Bilsky et al, 2000). More specifically, we have shown that O-linked glycosylation of a potent opioid hexapeptide does not interfere with the pharmacophore portion of the molecule, if the carbohydrate moiety is placed on the sixth amino acid residue (current results and Bilsky et al, 2000).…”

“…Suzuki and colleagues investigated the effects of glycosylation on the pharmacokinetics of arginine-vasopressin and oxytocin analogs following i.v. administration (Susaki et al, 1999;Suzuki et al, 1999a,b). Specific tissue uptake was dependent on both peptide sequence and the carbohydrate moiety added (Suzuki et al, 1999b).…”

“…The metabolites of the opioid glycopeptides, for example, would be small di-and tripeptides and sugars. Furthermore, the glycosylation approach may be applicable to any number of peptide molecules, although further testing will have to determine the effects of these modifications on a peptide by peptide basis (see, for example, Susaki et al, 1999;Suzuki et al, 1999a,b).…”

“…Recent studies with glycopeptides in artificial membrane systems indicate that the amphipathicity of the glycopeptides may be an important factor in BBB penetration (Palian et al, 2003). In addition, there is evidence that suggests that the type of glycosylation can alter tissue distribution patterns (Susaki et al, 1999;Suzuki et al, 1999a,b), BBB penetration unpublished results), and peptide/receptor interactions (Gysin and Schwyzer, 1983;Sargent et al, 1988;Palian and Polt, 2001).…”

Development of neuropeptide drugs that cross the blood-brain barrier

“…97,98,100 -102 BBB permeability studies of glycopeptides have indicated up to a three-fold increase in the rate of brain delivery, compared to the unglycosylated parent peptides. 97,101,102 Evidence also suggests that the type of glycosylation (i.e., mono-, di-, tri-glycosylation) can alter tissue distribution patterns, [103][104][105] BBB permeability, 102 and peptide/receptor interactions. 106,107 Peptides investigated to date include recombinant human erythropoietin, 108 leptin, 108 dermorphins 98 and metenkephalin analogs.…”