Inhibition of Human Immunodeficiency Virus Activity by Phosphorodithioate Oligodeoxycytidine

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1992 Jul 15

PMID 1378623

Citations 17

Authors

W S Marshall

G Beaton

C A Stein

M Matsukura

M H Caruthers

Affiliations

Soon will be listed here.

Abstract

Phosphorothioate oligodeoxynucleotides exert a sequence-independent cytoprotective effect against human immunodeficiency virus type 1 (HIV-1). We now report that phosphorodithioate-containing oligodeoxycytidines are very potent inhibitors of HIV-1 reverse transcriptase in vitro, as they exhibit an increasing inhibitory effect with length and number of phosphorodithioate internucleotide linkages. This inhibitory effect can be at least 30-fold greater with phosphorodithioate oligodeoxycytidine than for the corresponding phosphorothioate analog of similar length. In cell culture, phosphorodithioate oligodeoxycytidines are active inhibitors of syncytia formation and effectively inhibit de novo infection of target cells by HIV-1. Moreover, comparative experiments show that a deoxycytidine phosphorodithioate 14-mer is as effective an inhibitor of de novo infection as a phosphorothioate-containing 28-mer. Such potent inhibition by oligomers of relatively short length makes dithioate analogs an additional class of potential therapeutic agents against acquired immunodeficiency syndrome.

Citing Articles

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References

Mitsuya H, Yarchoan R, Broder S . Molecular targets for AIDS therapy. Science. 1990; 249(4976):1533-44. DOI: 10.1126/science.1699273. View

Caruthers M . Gene synthesis machines: DNA chemistry and its uses. Science. 1985; 230(4723):281-5. DOI: 10.1126/science.3863253. View

Stein C, Matsukura M, Subasinghe C, Broder S, Cohen J . Phosphorothioate oligodeoxynucleotides are potent sequence nonspecific inhibitors of de novo infection by HIV. AIDS Res Hum Retroviruses. 1989; 5(6):639-46. DOI: 10.1089/aid.1989.5.639. View

Agrawal S, Ikeuchi T, Sun D, SARIN P, Konopka A, Maizel J . Inhibition of human immunodeficiency virus in early infected and chronically infected cells by antisense oligodeoxynucleotides and their phosphorothioate analogues. Proc Natl Acad Sci U S A. 1989; 86(20):7790-4. PMC: 298156. DOI: 10.1073/pnas.86.20.7790. View

Sodroski J, Goh W, Rosen C, Campbell K, Haseltine W . Role of the HTLV-III/LAV envelope in syncytium formation and cytopathicity. Nature. 1986; 322(6078):470-4. DOI: 10.1038/322470a0. View

Stein C, Cohen J . Oligodeoxynucleotides as inhibitors of gene expression: a review. Cancer Res. 1988; 48(10):2659-68. View

Dalgleish A, Beverley P, Clapham P, Crawford D, Greaves M, Weiss R . The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984; 312(5996):763-7. DOI: 10.1038/312763a0. View

Zamecnik P, Stephenson M . Inhibition of Rous sarcoma virus replication and cell transformation by a specific oligodeoxynucleotide. Proc Natl Acad Sci U S A. 1978; 75(1):280-4. PMC: 411230. DOI: 10.1073/pnas.75.1.280. View

Stephenson M, Zamecnik P . Inhibition of Rous sarcoma viral RNA translation by a specific oligodeoxyribonucleotide. Proc Natl Acad Sci U S A. 1978; 75(1):285-8. PMC: 411231. DOI: 10.1073/pnas.75.1.285. View

10.

CLARK P, Ferris A, Miller D, Hizi A, Kim K, Mellini M . HIV-1 reverse transcriptase purified from a recombinant strain of Escherichia coli. AIDS Res Hum Retroviruses. 1990; 6(6):753-64. DOI: 10.1089/aid.1990.6.753. View

11.

Hizi A, McGill C, Hughes S . Expression of soluble, enzymatically active, human immunodeficiency virus reverse transcriptase in Escherichia coli and analysis of mutants. Proc Natl Acad Sci U S A. 1988; 85(4):1218-22. PMC: 279738. DOI: 10.1073/pnas.85.4.1218. View

12.

MAJUMDAR C, Stein C, Cohen J, Broder S, Wilson S . Stepwise mechanism of HIV reverse transcriptase: primer function of phosphorothioate oligodeoxynucleotide. Biochemistry. 1989; 28(3):1340-6. DOI: 10.1021/bi00429a060. View

13.

Cazenave C, Stein C, Loreau N, Thuong N, Neckers L, Subasinghe C . Comparative inhibition of rabbit globin mRNA translation by modified antisense oligodeoxynucleotides. Nucleic Acids Res. 1989; 17(11):4255-73. PMC: 317933. DOI: 10.1093/nar/17.11.4255. View

14.

Kulka M, Smith C, Aurelian L, Fishelevich R, Meade K, Miller P . Site specificity of the inhibitory effects of oligo(nucleoside methylphosphonate)s complementary to the acceptor splice junction of herpes simplex virus type 1 immediate early mRNA 4. Proc Natl Acad Sci U S A. 1989; 86(18):6868-72. PMC: 297951. DOI: 10.1073/pnas.86.18.6868. View

15.

Loke S, Stein C, Zhang X, Mori K, Nakanishi M, Subasinghe C . Characterization of oligonucleotide transport into living cells. Proc Natl Acad Sci U S A. 1989; 86(10):3474-8. PMC: 287160. DOI: 10.1073/pnas.86.10.3474. View

16.

Stein C, Subasinghe C, Shinozuka K, Cohen J . Physicochemical properties of phosphorothioate oligodeoxynucleotides. Nucleic Acids Res. 1988; 16(8):3209-21. PMC: 336489. DOI: 10.1093/nar/16.8.3209. View

17.

Agrawal S, Goodchild J, Civeira M, Thornton A, SARIN P, Zamecnik P . Oligodeoxynucleoside phosphoramidates and phosphorothioates as inhibitors of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1988; 85(19):7079-83. PMC: 282127. DOI: 10.1073/pnas.85.19.7079. View

18.

Matsukura M, Shinozuka K, Zon G, Mitsuya H, Reitz M, Cohen J . Phosphorothioate analogs of oligodeoxynucleotides: inhibitors of replication and cytopathic effects of human immunodeficiency virus. Proc Natl Acad Sci U S A. 1987; 84(21):7706-10. PMC: 299369. DOI: 10.1073/pnas.84.21.7706. View

19.

Matsukura M, Zon G, Shinozuka K, Robert-Guroff M, Shimada T, Stein C . Regulation of viral expression of human immunodeficiency virus in vitro by an antisense phosphorothioate oligodeoxynucleotide against rev (art/trs) in chronically infected cells. Proc Natl Acad Sci U S A. 1989; 86(11):4244-8. PMC: 287427. DOI: 10.1073/pnas.86.11.4244. View