Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 94 ·No. 6 ·1997-03-18 ·Pages 2620-5

Agrawal S, Jiang Z, Zhao Q, Shaw D, Cai Q, Roskey A, Channavajjala L, Saxinger C, Zhang R

Abstract

Antisense oligonucleotides are being evaluated in clinical trials as novel therapeutic agents. To further improve the properties of antisense oligonucleotides, we have designed mixed-backbone oligonucleotides (MBOs) that contain phosphorothioate segments at the 3' and 5' ends and have a modified oligodeoxynucleotide or oligoribonucleotide segment located in the central portion of the oligonucleotide. Some of these MBOs indicate improved properties compared with phosphorothioate oligodeoxynucleotides with respect to affinity to RNA, RNase H activation, and anti-HIV activity. In addition, more acceptable pharmacological, in vivo degradation and pharmacokinetic profiles were obtained with these MBOs.

MeSH Terms

Animals Anti-HIV Agents/chemistry,pharmacokinetics,pharmacology Base Sequence Blood Coagulation/drug effects Cell Line Cells, Cultured Drug Design HIV-1/drug effects,physiology Hemolysis/drug effects Humans Kidney/metabolism Kinetics Lymphocyte Activation Lymphocytes/drug effects,immunology Male Metabolic Clearance Rate Mice Nucleic Acid Denaturation Oligodeoxyribonucleotides Oligonucleotides, Antisense/chemistry,pharmacokinetics,pharmacology Oligoribonucleotides Rats Rats, Sprague-Dawley Ribonuclease H/metabolism Spleen Thionucleotides Triazines Virus Replication/drug effects

Chemicals

Anti-HIV Agents Oligodeoxyribonucleotides Oligonucleotides, Antisense Oligoribonucleotides Thionucleotides Triazines 4-azido-7-phenylpyrazolo-(1,5a)-1,3,5-triazine Ribonuclease H

Authors & Affiliations

9 authors, click to expand affiliations / ORCID

Agrawal S

Hybridon Inc., Cambridge, MA 02139, USA.

Jiang Z

Zhao Q

Shaw D

Cai Q

Roskey A

Channavajjala L

Saxinger C

Zhang R

References (17)

17 references, click to expand

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Article Info

Journal

Proceedings of the National Academy of Sciences of the United States of America

Abbr.

Proc Natl Acad Sci U S A

ISSN

0027-8424

DOI

10.1073/pnas.94.6.2620

Published

1997-03-18

Pages

2620-5

Language

English

Region

United States

NLM ID

7505876

PMCID

PMC20138

Subset

External Links

PubMed source DOI: 10.1073/pnas.94.6.2620 PMC Full Text View journal details

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Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies.

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