Targeted Delivery of Antisense Oligonucleotides Using Neurotensin Peptides

Journal of Medicinal Chemistry
Mehran NikanT P Prakash

Abstract

Despite recent advances, targeted delivery of therapeutic oligonucleotide to extra-hepatic tissues continues to be a challenging endeavor and efficient ligand-receptor systems need to be identified. To determine the feasibility of using neurotensin to improve the productive uptake of antisense oligonucleotides (ASO), we synthesized neurotensin-ASO conjugates and evaluated their cellular uptake and activity in cells and in mice. We performed a comprehensive structure-activity relationship study of the conjugates and determined the influence of ASO charge, ASO length, peptide charge, linker chemistry and ligand identity on receptor binding and internalization. We identified a modified neurotensin peptide capable of improving the cellular uptake and activity of gapmer ASOs in sortilin expressing cells (sixfold) and in spinal cord in mice (twofold). Neurotensin conjugation also improved the potency of morpholino ASO designed to correct splicing of survival motor neuron pre-mRNA in the cortex and striatum after intracerebroventricular injection. Neurotensin-mediated targeted delivery represents a possible approach for enhancing the potency of ASOs with diverse nucleic acid modifications.

References

May 24, 1991·Science·B J CalnanA D Frankel
Oct 1, 1995·Cellular and Molecular Neurobiology·J P Vincent
Jun 1, 1997·Antisense & Nucleic Acid Drug Development·J Summerton, D Weller
May 21, 1998·Antisense & Nucleic Acid Drug Development·S T Crooke
Feb 2, 1999·The EMBO Journal·C Munck PetersenP Madsen
Sep 15, 2004·The Journal of Biological Chemistry·Uffe B WestergaardClaus Munck Petersen
Oct 19, 2007·Proceedings of the National Academy of Sciences of the United States of America·Jeremy M BaskinCarolyn R Bertozzi
Jan 6, 2009·Nature Structural & Molecular Biology·Esben M QuistgaardSøren S Thirup
Jan 9, 2010·Annual Review of Pharmacology and Toxicology·C Frank Bennett, Eric E Swayze
Sep 4, 2010·Medicinal Research Reviews·Sumit Majumdar, Teruna J Siahaan
Jul 6, 2014·Protein Science : a Publication of the Protein Society·Esben M QuistgaardSøren S Thirup
Sep 9, 2015·Bioconjugate Chemistry·Alba MascarinThomas L Mindt
Jul 3, 2016·Journal of Controlled Release : Official Journal of the Controlled Release Society·Tsukasa SugoHirokazu Matsumoto
Aug 16, 2016·European Journal of Pharmaceutics and Biopharmaceutics : Official Journal of Arbeitsgemeinschaft Für Pharmazeutische Verfahrenstechnik E.V·Matt GoodingCaitriona M O'Driscoll
Jan 13, 2017·Nucleic Acid Therapeutics·Stanley T Crooke
Mar 23, 2017·Journal of Biophysics·P V G M RathnayakeR J K U Ranatunga
Jun 15, 2017·Chembiochem : a European Journal of Chemical Biology·Maria TaskovaKira Astakhova
Dec 15, 2017·Nucleic Acids Research·Xiulong Shen, David R Corey
Apr 5, 2018·Cell Metabolism·Stanley T CrookeBrenda F Baker
Oct 23, 2018·Science Advances·C ÄmmäläS Andersson

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Citations

May 18, 2021·Frontiers in Molecular Biosciences·Olga KhorkovaClaes Wahlestedt
May 23, 2021·Trends in Pharmacological Sciences·Tufan GökirmakPunit P Seth

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