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Oligonucleotides — A better alternative to interferon?
Medical Hypotheses 7: 1091-1094, 1981
OLIGONUCLEOTIDES
- A BETTER
Department of W.S. Adamus. Boehringer Ingelheim, 6507
ALTERNATIVE
TO
INTERFERON?
Clinical Pharmacology, Ingelheim, West Germany.
ABSTRACT -------Interferon and interferon research are very expensive. A cheaper alternative to interferon is worth looking for. A possible alternative may be oligoadenylic acid or other oligonucleotides. Oligoadenylic acid, Key words: Interferon, LMWIT-Low Molecular Oligonucleotides, Weight Inhibitor of Translation. INTRODUCTION -----------Interferon is a glycoprotein with antiviral, immunomodulatory and antiproliferative properties. This exciting substance was discovered in 1957 by A.Issacs High costs and the small amount and J.Lindenmann. of interferon available limit therapeutic trials. It would be of importance to have available cheap sources of interferon or alternative ways of raising interferon levels. Three enzymatic pathways interferon action (1,2). One
of these
pathways
are
probably
is considered
Oligonucleotide inhibitor of protein ------_____---_______--~~~~--~~~~~~~
involved
in
below. synthesis -------A
Recently it was reported that interferon acts in part by stimulating formation of 2'5'-oligoadenylic Weight Inhibitor of acid /LMWIT - Low Molecular
1091
Translation/, an oligonucleotide of unusual structure. Interferon-induced oligonucleotide synthetase is responsible for the formation of ppp A2'p5'A2'p5'A. This oligonucleotide activates a cellular endonuclease, which preferentially degrades viral mRNA, but not at subnanomolar cellular mRNA, and is effective concentrations (3-9). It has also been synthesised by H.Sawai et al. (10). T.Martin and I.Kerr suggest use of this oligonucleotide as an alternative to interferon (11). Other oligonucleotides as inhibitors of protein ---_---------------------------------------synthesis. -------There are data that other oligonucleotides may affect translation (12) or inhibit virus reproduction (13). /personal communication/ About 7 years ago, W.S.Adamus examined the influence of oligodeoxyand oligoribonucleotides on transformation. The oligonucleotides were obtained with the help of specific enzymes /DNAfrom herring DNA and yeast RNA. The ase I, RNA-ase/ products of hydrolysis were separated on a chromatographic column filled with Sephadex G-50. The influence of transformation was examined on cultured chick embryo cells. It was found that high molecular weight oligonucleotides /more as 6 nucleotides in chain/ can stimulate transformation, but low molecular weight oligonucleotides /2 - 6 nucleotides in chain/ stop the division of transformed cells and do not stop the division of normal cells. The molecular structure of these oligonucleotides was not The latest experiments with low molecular identified. weight oligonucleotides, in mice bearing Ehrlich ascites tumor cells lead to the assumption that this group of substances may possess antiproliferative properties not only in vitro but also in vivo (14). CONCLUSION ---------The hypothesis of Martin and Kerr that oligonucleotides /in this case oligoadenylic acid/ represent alternatives to interferon which are both cheaper and in greater supply requires further experiments to confirm or to exclude this possibility. It should also be examined whether apart from oligoadenylic could be involved in acid, other oligonucleotides
1092
the translational cell.
or inhibitory
processes
in the
We know that the physiological role of nucleic acids in cellular regulatory processes is greater than The first experiments with of single nucleotides. oligonucleotides show that they may play a greater role in cellular regulatory apparatus than single nucleotides. They may be an intermediate functional stage between nucleic acids and nucleotides. Nowadays, single nucleotides are used as therapeutics in the antivirus and antitumor therapy. It is possible that oligonucleotides may prove of greater therapeutic value than single nucleotides. 1.
2.
3.
4.
5.
6.
7.
8.
Stewart WE. The interferon system. Springer Verlag, 1979. Hirsch MS, Swartz MN. Antiviral agents (second of two parts). The New England Journal of Medicine 302:17, 1980. Baglioni C, Minks MA, Maroney PA. Interferon action may be mediated by activation of a nuclease by ppp A2'p5'A2'p5'A. Nature 273:684, 1978. Ball LA, White CN. Oligonucleotide inhibitor of protein synthesis made in extracts of interferon-treated chick embryo cells. Comparison with the mouse low molecular weight inhibitor. Proc.Nat.Acad.Sci.USA 75:1167, 1979. Clemens MJ, Williams BRG. Inhibition of cell-free protein synthesis by ppp A2'p5'A2'p5'A: a novel oligonucleotide synthesized by interferon-treated L cell extracts. Cell 13:565, 1978. Eppstein DA, Peterson TC, Samuel CE. Mechanism of interferon action: synthesis and activity of the interferon-mediated low molecular weight oligonucleotide from murine and human cells. Virology 989, 1979. Slattery E, Ghash N, Samanta H, Lengyel P. Interferon, double-stranded RNA, and RNA degradation : activation of an endonuclease by (2'-5') A. Proc.Natl.Acad.Sci.USA 76:4778, 1979. Baglioni C, Maroney P. Mechanism of action The Journal of Biological of human interferons. Chemistry 255:8390, 1980.
1093
9.
10.
11. 12.
13.
14.
The 2-5 A (ppp A2'p5' Williams BRG, Kerr IM. A2lp5'A) system in interferon-treated and TIBS 138, 1980. control cells. Synthesis.of Sawai H, Shibata T, Ohno M. oligonucleotide inhibitor of protein synthesis: Tetrahedron Letters 47:4573, ppp A2'p5'A2'p5'A. 1979. Communication in IMS Pharmaceutical Marketletter 15, 1980. 12, September Lee-Huang S, Sierra JM, Naranjo R, Filipowicz Eucariotic oligonucleotides affecting W, Ochoa S. Archives of Biochemistry and mRNA translation. Biophysics 180:276, 1977. Die Bedeutung der chemischen Synthese Koster H. Arzneimittel von DNS fiir die Gentechnologie. Forschung/Drug Research 30:548, 1980. Unpublished data, available from Adamus WS. the author.
1094
OLIGONUCLEOTIDES
- A BETTER
Department of W.S. Adamus. Boehringer Ingelheim, 6507
ALTERNATIVE
TO
INTERFERON?
Clinical Pharmacology, Ingelheim, West Germany.
ABSTRACT -------Interferon and interferon research are very expensive. A cheaper alternative to interferon is worth looking for. A possible alternative may be oligoadenylic acid or other oligonucleotides. Oligoadenylic acid, Key words: Interferon, LMWIT-Low Molecular Oligonucleotides, Weight Inhibitor of Translation. INTRODUCTION -----------Interferon is a glycoprotein with antiviral, immunomodulatory and antiproliferative properties. This exciting substance was discovered in 1957 by A.Issacs High costs and the small amount and J.Lindenmann. of interferon available limit therapeutic trials. It would be of importance to have available cheap sources of interferon or alternative ways of raising interferon levels. Three enzymatic pathways interferon action (1,2). One
of these
pathways
are
probably
is considered
Oligonucleotide inhibitor of protein ------_____---_______--~~~~--~~~~~~~
involved
in
below. synthesis -------A
Recently it was reported that interferon acts in part by stimulating formation of 2'5'-oligoadenylic Weight Inhibitor of acid /LMWIT - Low Molecular
1091
Translation/, an oligonucleotide of unusual structure. Interferon-induced oligonucleotide synthetase is responsible for the formation of ppp A2'p5'A2'p5'A. This oligonucleotide activates a cellular endonuclease, which preferentially degrades viral mRNA, but not at subnanomolar cellular mRNA, and is effective concentrations (3-9). It has also been synthesised by H.Sawai et al. (10). T.Martin and I.Kerr suggest use of this oligonucleotide as an alternative to interferon (11). Other oligonucleotides as inhibitors of protein ---_---------------------------------------synthesis. -------There are data that other oligonucleotides may affect translation (12) or inhibit virus reproduction (13). /personal communication/ About 7 years ago, W.S.Adamus examined the influence of oligodeoxyand oligoribonucleotides on transformation. The oligonucleotides were obtained with the help of specific enzymes /DNAfrom herring DNA and yeast RNA. The ase I, RNA-ase/ products of hydrolysis were separated on a chromatographic column filled with Sephadex G-50. The influence of transformation was examined on cultured chick embryo cells. It was found that high molecular weight oligonucleotides /more as 6 nucleotides in chain/ can stimulate transformation, but low molecular weight oligonucleotides /2 - 6 nucleotides in chain/ stop the division of transformed cells and do not stop the division of normal cells. The molecular structure of these oligonucleotides was not The latest experiments with low molecular identified. weight oligonucleotides, in mice bearing Ehrlich ascites tumor cells lead to the assumption that this group of substances may possess antiproliferative properties not only in vitro but also in vivo (14). CONCLUSION ---------The hypothesis of Martin and Kerr that oligonucleotides /in this case oligoadenylic acid/ represent alternatives to interferon which are both cheaper and in greater supply requires further experiments to confirm or to exclude this possibility. It should also be examined whether apart from oligoadenylic could be involved in acid, other oligonucleotides
1092
the translational cell.
or inhibitory
processes
in the
We know that the physiological role of nucleic acids in cellular regulatory processes is greater than The first experiments with of single nucleotides. oligonucleotides show that they may play a greater role in cellular regulatory apparatus than single nucleotides. They may be an intermediate functional stage between nucleic acids and nucleotides. Nowadays, single nucleotides are used as therapeutics in the antivirus and antitumor therapy. It is possible that oligonucleotides may prove of greater therapeutic value than single nucleotides. 1.
2.
3.
4.
5.
6.
7.
8.
Stewart WE. The interferon system. Springer Verlag, 1979. Hirsch MS, Swartz MN. Antiviral agents (second of two parts). The New England Journal of Medicine 302:17, 1980. Baglioni C, Minks MA, Maroney PA. Interferon action may be mediated by activation of a nuclease by ppp A2'p5'A2'p5'A. Nature 273:684, 1978. Ball LA, White CN. Oligonucleotide inhibitor of protein synthesis made in extracts of interferon-treated chick embryo cells. Comparison with the mouse low molecular weight inhibitor. Proc.Nat.Acad.Sci.USA 75:1167, 1979. Clemens MJ, Williams BRG. Inhibition of cell-free protein synthesis by ppp A2'p5'A2'p5'A: a novel oligonucleotide synthesized by interferon-treated L cell extracts. Cell 13:565, 1978. Eppstein DA, Peterson TC, Samuel CE. Mechanism of interferon action: synthesis and activity of the interferon-mediated low molecular weight oligonucleotide from murine and human cells. Virology 989, 1979. Slattery E, Ghash N, Samanta H, Lengyel P. Interferon, double-stranded RNA, and RNA degradation : activation of an endonuclease by (2'-5') A. Proc.Natl.Acad.Sci.USA 76:4778, 1979. Baglioni C, Maroney P. Mechanism of action The Journal of Biological of human interferons. Chemistry 255:8390, 1980.
1093
9.
10.
11. 12.
13.
14.
The 2-5 A (ppp A2'p5' Williams BRG, Kerr IM. A2lp5'A) system in interferon-treated and TIBS 138, 1980. control cells. Synthesis.of Sawai H, Shibata T, Ohno M. oligonucleotide inhibitor of protein synthesis: Tetrahedron Letters 47:4573, ppp A2'p5'A2'p5'A. 1979. Communication in IMS Pharmaceutical Marketletter 15, 1980. 12, September Lee-Huang S, Sierra JM, Naranjo R, Filipowicz Eucariotic oligonucleotides affecting W, Ochoa S. Archives of Biochemistry and mRNA translation. Biophysics 180:276, 1977. Die Bedeutung der chemischen Synthese Koster H. Arzneimittel von DNS fiir die Gentechnologie. Forschung/Drug Research 30:548, 1980. Unpublished data, available from Adamus WS. the author.
1094