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�й����ﻯѧ���������ѧ�� 1999, Vol. 15 Issue (04 ):604-604     DOI:
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Effect of Chemical Modifications on the Stability and Anti influenza A Virus Activity of Antisense Oligonucleotide
CHEN Zhongbin, WANG Shengqi, ZHU Baozhen, SUN Zhixian (Beijing Institute of Radiation Medicine,Beijing 100850)

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Abstract�� Synthetic oligonucleotides complementary to messenger RNA have shown promise as therapeutic agents for various diseases, especially for cancer and virus infection. Phosphorothioate antisense oligodeoxynucleotide (ASODN), ODN No.4, targeted to part of the 5�� end sequences which are common to the eight RNAs of type A influenza virus was previously reported to exhibit significant antiviral activity. To further improve the stability and antiviral activity of ODN No.4, ASODN analogs:(1) phosphorothioate ODN No.4, (2)phosphorothioate ODN No.4 with 3�� end modified by phosphonate or cholesterol, (3) phosphodiester ODN No.4, (4)phosphodiester ODN No.4 with 3�� end conjugated with phosphonate or cholesterol and (5) mixed backbone oligonucleotide (MBO) that contained phosphorothioate segments at the 3�� and 5�� end and had phosphodiester oligodeoxynucleotide located in the central portion of the oligonucleotide were synthesized, and then the stability, in vitro cytotoxicity and anti influenza A virus activity of these ASODNs were assayed. It was found that mixed backbone oligonucleotide, phosphorothioate ASODN and the modified analogs with 3�� end by phosphonate or cholesterol showed magnificantly high stability when incubated with mice serum, MDCK lysate or DMEM culture medium containing 2% inactivated fetal bovine serum. On the contrary, the phosphodiester ASODN and its analogs with 3�� end modified by phosphonate or cholesterol showed time dependent degradation. All these ASODNs remained stable in water at all the time points assayed. All modified ASODN analogs showed no cytotoxicity in MDCK cells. The phosphorothioate ASODN and its modified analogs with 3�� end by phosphonate or cholesterol exhibited high anti influenza virus activity in a dose dependent manner, and at 1 ��mol/L the inhibition rate was 55 0%, 32 9% and 56 8% respectively. Incorporation of cholesterols onto phosphorothioate ASODN could markedly enhance its antiviral activity. The phosphodiester ASODN and its modified analogs and MBO showed low antiviral activity with inhibition rate no more than 25% at 1 ��mol/L. These results suggest that the phosphorothioate ASODN and its modified analogs with 3�� end by phosphonate or cholesterol can present the most suitable chemical modification of anti influenza virus antisense oligonucleotide for the treatment of human influenza with high stability and low cytotoxicity.
Keywords�� Antisense oligonucleotide   Chemical modification   In vitro stability   Cytotoxicity   Anti influenza virus activity      
Received 1998-07-20;
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���ұ�.��ѧ���ζԷ���Ѻ������ȶ��Լ������в������Ե�Ӱ�� [J]  �й����ﻯѧ���������ѧ��, 1999,V15(04 ): 604-604
.Effect of Chemical Modifications on the Stability and Anti influenza A Virus Activity of Antisense Oligonucleotide [J]  Chinese Journal of Biochemistry and Molecular Biol, 1999,V15(04 ): 604-604
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