Literature DB >> 27161280

Synergistic effect of phosphorothioate, 5'-vinylphosphonate and GalNAc modifications for enhancing activity of synthetic siRNA.

Thazha P Prakash1, Garth A Kinberger2, Heather M Murray2, Alfred Chappell2, Stan Riney2, Mark J Graham2, Walt F Lima2, Eric E Swayze2, Punit P Seth2.   

Abstract

Chemical modifications are essential to improve metabolic stability and pharmacokinetic properties of siRNA to enable their systemic delivery. We investigated the effect of combing the phosphorothioate (PS) modification with metabolically stable phosphate analog (E)-5'-vinylphosphonate and GalNAc cluster conjugation on the activity of fully 2'-modified siRNA in cell culture and mice. Our data suggest that integrating multiple chemical approaches in one siRNA molecule improved potency 5-10 fold and provide a roadmap for developing more efficient siRNA drugs.
Copyright © 2016 Elsevier Ltd. All rights reserved.

Entities:  

Keywords:  3′-GalNAc cluster; 5′-Vinylphosphonate siRNA; Alternating F/OMe siRNA; Fully modified siRNA; siRNA phosphorothioates

Mesh：

Substances：

Year:  2016        PMID： 27161280     DOI： 10.1016/j.bmcl.2016.04.063

Source DB:  PubMed          Journal:  Bioorg Med Chem Lett        ISSN： 0960-894X            Impact factor:   2.823


  25 in total

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Review 2.  GalNAc-siRNA Conjugates: Leading the Way for Delivery of RNAi Therapeutics.

Authors:  Aaron D Springer; Steven F Dowdy
Journal:  Nucleic Acid Ther       Date:  2018-05-24       Impact factor: 5.486

Review 3.  The chemical evolution of oligonucleotide therapies of clinical utility.

Authors:  Anastasia Khvorova; Jonathan K Watts
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Review 4.  Improving siRNA Delivery In Vivo Through Lipid Conjugation.

Authors:  Maire F Osborn; Anastasia Khvorova
Journal:  Nucleic Acid Ther       Date:  2018-05-10       Impact factor: 5.486

Review 5.  Therapeutic RNA-silencing oligonucleotides in metabolic diseases.

Authors:  Algera Goga; Markus Stoffel
Journal:  Nat Rev Drug Discov       Date:  2022-02-24       Impact factor: 84.694

6.  Structurally constrained phosphonate internucleotide linkage impacts oligonucleotide-enzyme interaction, and modulates siRNA activity and allele specificity.

Authors:  Ken Yamada; Samuel Hildebrand; Sarah M Davis; Rachael Miller; Faith Conroy; Ellen Sapp; Jillian Caiazzi; Julia F Alterman; Loic Roux; Dimas Echeverria; Matthew R Hassler; Edith L Pfister; Marian DiFiglia; Neil Aronin; Anastasia Khvorova
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Review 7.  Leading RNA Interference Therapeutics Part 2: Silencing Delta-Aminolevulinic Acid Synthase 1, with a Focus on Givosiran.

Authors:  Pedro Renato de Paula Brandão; Simoneide S Titze-de-Almeida; Ricardo Titze-de-Almeida
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8.  Optimized Cholesterol-siRNA Chemistry Improves Productive Loading onto Extracellular Vesicles.

Authors:  Reka Agnes Haraszti; Rachael Miller; Marie-Cecile Didiot; Annabelle Biscans; Julia F Alterman; Matthew R Hassler; Loic Roux; Dimas Echeverria; Ellen Sapp; Marian DiFiglia; Neil Aronin; Anastasia Khvorova
Journal:  Mol Ther       Date:  2018-06-21       Impact factor: 11.454

9.  Structural Analysis of Human Argonaute-2 Bound to a Modified siRNA Guide.

Authors:  Nicole T Schirle; Garth A Kinberger; Heather F Murray; Walt F Lima; Thazha P Prakash; Ian J MacRae
Journal:  J Am Chem Soc       Date:  2016-07-12       Impact factor: 15.419

10.  Small circular interfering RNAs (sciRNAs) as a potent therapeutic platform for gene-silencing.

Authors:  Hartmut Jahns; Rohan Degaonkar; Peter Podbevsek; Swati Gupta; Anna Bisbe; Krishna Aluri; John Szeto; Pawan Kumar; Sarah LeBlanc; Tim Racie; Christopher R Brown; Adam Castoreno; Dale C Guenther; Vasant Jadhav; Martin A Maier; Janez Plavec; Martin Egli; Muthiah Manoharan; Ivan Zlatev
Journal:  Nucleic Acids Res       Date:  2021-10-11       Impact factor: 16.971
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