PMID: 11906267Mar 22, 2002Paper

Design of a targeted peptide nucleic acid prodrug to inhibit hepatic human microsomal triglyceride transfer protein expression in hepatocytes

Bioconjugate Chemistry
E A BiessenT J van Berkel

Abstract

In this study, we present the design and synthesis of an antisense peptide nucleic acid (asPNA) prodrug, which displays an improved biodistribution profile and an equally improved capacity to reduce the levels of target mRNA. The prodrug, K(GalNAc)(2)-asPNA, comprised of a 14-mer sequence complementary to the human microsomal triglyceride transfer protein (huMTP) gene, conjugated to a high-affinity tag for the hepatic asialoglycoprotein receptor (K(GalNAc)(2)). The prodrug was avidly bound and rapidly internalized by HepG2s. After iv injection into mice, K(GalNAc)(2)-asPNA accumulated in the parenchymal liver cells to a much greater extent than nonconjugated PNA (46% +/- 1% vs 3.1% +/- 0.5% of the injected dose, respectively). The prodrug was able to reduce MTP mRNA levels in HepG2 cells by 35-40% (P < 0.02) at 100 nM in an asialoglycoprotein receptor- and sequence-dependent fashion. In conclusion, hepatocyte-targeted PNA prodrugs combine a greatly improved tropism with an enhanced local intracellular availability and activity, making them attractive therapeutics to lower the expression level of hepatic target genes such as MTP.

Citations

Oct 14, 2011·Bioconjugate Chemistry·Rudolph L JulianoOsamu Nakagawa
Dec 15, 2016·Bioconjugate Chemistry·Xiangang HuangBastien Castagner
Dec 22, 2009·Chemical Communications : Chem Comm·Pim G A JanssenAlbertus P H J Schenning
Apr 18, 2018·Nature Structural & Molecular Biology·Judy Lieberman
Dec 4, 2004·Cancer Gene Therapy·Xiaohong OuAnren Kuang
Dec 11, 2002·Liver Transplantation : Official Publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society·Betsy T KrenClifford J Steer
Jul 10, 2003·Chembiochem : a European Journal of Chemical Biology·Sabine M W van RossenbergErik A L Biessen
Nov 11, 2005·American Journal of Therapeutics·Nick Giannoukakis, Massimo Trucco
Oct 31, 2006·The Journal of the Acoustical Society of America·King ChungKyle N Acker
Sep 19, 2002·The Journal of Biological Chemistry·Sabine M W Van RossenbergErik A L Biessen
Dec 31, 2020·Pharmaceuticals·Stefano VolpiRoberto Corradini
Aug 10, 2021·Beilstein Journal of Organic Chemistry·Nikita BrodyaginEriks Rozners
Feb 9, 2011·The Journal of Organic Chemistry·Takeshi YamadaKallanthottathil G Rajeev
Oct 15, 2021·Arteriosclerosis, Thrombosis, and Vascular Biology·Erik A L Biessen, Theo J C Van Berkel

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