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

March 18, 1997
94 (6) 2620-2625

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.

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Acknowledgments

We thank Y. Li, B. Chambless, Yufeng Li, and L. High for technical assistance. The safety studies of oligonucleotides were carried out at Frederick Research Center, Frederick, MD.

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Information & Authors

Information

Published in

The cover image for PNAS Vol.94; No.6
Proceedings of the National Academy of Sciences
Vol. 94 | No. 6
March 18, 1997
PubMed: 9122245

Classifications

Submission history

Received: October 2, 1996
Accepted: December 30, 1996
Published online: March 18, 1997
Published in issue: March 18, 1997

Keywords

  1. pharmacokinetics
  2. anti-HIV agents
  3. coagulation
  4. hemolytic complement

Acknowledgments

We thank Y. Li, B. Chambless, Yufeng Li, and L. High for technical assistance. The safety studies of oligonucleotides were carried out at Frederick Research Center, Frederick, MD.

Authors

Affiliations

Sudhir Agrawal
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Zhiwei Jiang
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Qiuyan Zhao
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Denise Shaw
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Qiuyin Cai
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Allysen Roskey
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Lakshmi Channavajjala
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Carl Saxinger
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892
Ruiwen Zhang
Hybridon Inc., 620 Memorial Drive, Cambridge, MA 02139; Department of Medicine, Division of Hematology and Oncology, and Department of Pharmacology and Toxicology and Division of Clinical Pharmacology, Comprehensive Cancer Center and Center for AIDS Research, University of Alabama at Birmingham, AL 35294; and Division of Basic Sciences, National Cancer Institute, Building 37, Room 6B04, Bethesda, MD 20892

Notes

To whom reprint requests should be addressed.
Paul Zamecnik, Worcester Foundation for Biomedical Research, Shrewsbury, MA

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    Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: In vitro and in vivo studies
    Proceedings of the National Academy of Sciences
    • Vol. 94
    • No. 6
    • pp. 2091-2765

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