Skip to main content
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1979 Mar;76(3):1018–1021. doi: 10.1073/pnas.76.3.1018

Interferon induction: a conformational hypothesis.

D L Miles, D W Miles, H Eyring
PMCID: PMC383178  PMID: 286290

Abstract

The ability of polynucleotides or polynucleotide duplexes such as poly(I).poly(C) to induce interferon production is proposed to depend on the existence of certain stable glycosidic orientations. It appears that a slight increase in instability of 1--3 kcal/mole (1 cal = 4.184 J) in the conformational regions near 20 degrees, 80 degrees, and 160 degrees leads to a loss of potency with respect to interferon induction. Thus, it is proposed that, for a polynucleotide to exist in the overall conformation necessary for interferon induction, stability of glycosidic orientations near 20 degrees, 80 degrees, and 160 degrees may be necessary to confer flexibility and activity on polynucleotide structures. This proposed conformational triad of stable conformational regions essential to interferon induction is based on the results of conformational energy calculations of the glycoside rotational profiles of adenosine, 7-deazaadenosine, inosine, and 7-deazainosine, as well as the conformational properties of other purine nucleoside analogs, and on inferences derived from calculations about the conformational effect in polynucleotides of removing the 2'-OH group.

Full text

PDF
1018

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Arnott S., Fuller W., Hodgson A., Prutton I. Molecular conformations and structure transitions of RNA complementary helices and their possible biological significance. Nature. 1968 Nov 9;220(5167):561–564. doi: 10.1038/220561a0. [DOI] [PubMed] [Google Scholar]
  2. Arnott S., Hukins D. W., Dover S. D., Fuller W., Hodgson A. R. Structures of synthetic polynucleotides in the A-RNA and A'-RNA conformations: x-ray diffraction analyses of the molecular conformations of polyadenylic acid--polyuridylic acid and polyinosinic acid--polycytidylic acid. J Mol Biol. 1973 Dec 5;81(2):107–122. doi: 10.1016/0022-2836(73)90183-6. [DOI] [PubMed] [Google Scholar]
  3. Baron S., Bogomolova N. N., Billiau A., Levy H. B., Buckler C. E., Stern R., Naylor R. Induction of interferon by preparations of synthetic single-stranded RNA. Proc Natl Acad Sci U S A. 1969 Sep;64(1):67–74. doi: 10.1073/pnas.64.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bobst A. M., Torrence P. F., Kouidou S., Witkop B. Dependence of interferon induction on nucleic acid conformation. Proc Natl Acad Sci U S A. 1976 Nov;73(11):3788–3792. doi: 10.1073/pnas.73.11.3788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. De Clercq E., Billiau A., Hattori M., Ikehara M. Inhibition of oncornavirus functions by poly (2-methylthioinosinic acid). Nucleic Acids Res. 1975 Dec;2(12):2305–2313. doi: 10.1093/nar/2.12.2305. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. De Clercq E., Hattori M., Ikehara M. Antiviral activity of polynucleotides: copolymers of inosinic acid and N2-dimethylguanylic of 2-methylthioinosinic acid. Nucleic Acids Res. 1975 Jan;2(1):121–129. doi: 10.1093/nar/2.1.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Clercq E., Merigan T. C. Requirement of a stable secondary structure for the antiviral activity of polynucleotides. Nature. 1969 Jun 21;222(5199):1148–1152. doi: 10.1038/2221148a0. [DOI] [PubMed] [Google Scholar]
  8. De Clercq E., Torrence P. F., Witkop B. Interferon induction by synthetic polynucleotides: importance of purine N-7 and strandwise rearrangement. Proc Natl Acad Sci U S A. 1974 Jan;71(1):182–186. doi: 10.1073/pnas.71.1.182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. De Maeyer-Guignard J., Thang M. N., De Maeyer E. Binding of mouse interferon to polynucleotides. Proc Natl Acad Sci U S A. 1977 Sep;74(9):3787–3790. doi: 10.1073/pnas.74.9.3787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Einstein R., Angus J. A., Cobbin L. B., Maguire M. H. Separation of vasodilator and negative chronotropic actions in analogues of adenosine. Eur J Pharmacol. 1972 Aug;19(2):246–250. doi: 10.1016/0014-2999(72)90016-7. [DOI] [PubMed] [Google Scholar]
  11. Fukui T., Kakiuchi N., Ikehara M. Polynucleotides. XLIV. Synthesis and properties of poly (2-azaadenylic acid) and poly(2-azainosinic acid). Biochim Biophys Acta. 1978 Sep 27;520(2):441–451. doi: 10.1016/0005-2787(78)90241-1. [DOI] [PubMed] [Google Scholar]
  12. Gregory R. L. Cognitive contours. Nature. 1972 Jul 7;238(5358):51–52. doi: 10.1038/238051a0. [DOI] [PubMed] [Google Scholar]
  13. Howard F. B., Frazier J., Miles H. T. Formation of polynucleotide helices having purine nucleotide residues in a syn configuration. J Biol Chem. 1972 Oct 25;247(20):6733–6735. [PubMed] [Google Scholar]
  14. Jovin T. M. Recognition mechanisms of DNA-specific enzymes. Annu Rev Biochem. 1976;45:889–920. doi: 10.1146/annurev.bi.45.070176.004325. [DOI] [PubMed] [Google Scholar]
  15. Miles D. L., Miles D. W., Eyring H. Conformational basis for the activation of adenylate cyclase by adenosine. Proc Natl Acad Sci U S A. 1977 Jun;74(6):2194–2198. doi: 10.1073/pnas.74.6.2194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Miles D. L., Miles D. W., Redington P., Eyring H. A conformational basis for the selective action of ara-adenine. J Theor Biol. 1977 Aug 7;67(3):499–514. doi: 10.1016/0022-5193(77)90052-2. [DOI] [PubMed] [Google Scholar]
  17. Miles D. L., Miles D. W., Redington P., Eyring H. Theoretical studies of the conformational properties of ribavirin. Proc Natl Acad Sci U S A. 1976 Dec;73(12):4257–4260. doi: 10.1073/pnas.73.12.4257. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Miles D. W., Townsend L. B., Miles D. L., Eyring H. Conformation of nucleosides: circular dichroism study on the syn-anti conformational equilibrium of 2-substituted benzimidazole nucleosides. Proc Natl Acad Sci U S A. 1979 Feb;76(2):553–556. doi: 10.1073/pnas.76.2.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Olson W. K. Spatial configuration of ordered polynucleotide chains: a novel double helix. Proc Natl Acad Sci U S A. 1977 May;74(5):1775–1779. doi: 10.1073/pnas.74.5.1775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Olsson R. A. Ligand binding to the adenine analogue binding protein of the rabbit erythrocyte. Biochemistry. 1978 Jan 24;17(2):367–375. doi: 10.1021/bi00595a027. [DOI] [PubMed] [Google Scholar]
  21. Pitha P. M., Pitha J. Interferon induction by single-stranded polynucleotides modified with polybases. J Gen Virol. 1974 Aug;24(2):385–390. doi: 10.1099/0022-1317-24-2-385. [DOI] [PubMed] [Google Scholar]
  22. Rodley G. A., Scobie R. S., Bates R. H., Lewitt R. M. A possible conformation for double-stranded polynucleotides. Proc Natl Acad Sci U S A. 1976 Sep;73(9):2959–2963. doi: 10.1073/pnas.73.9.2959. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Sasisekharan V., Pattabiraman N., Gupta G. Some implications of an alternative structure for DNA. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4092–4096. doi: 10.1073/pnas.75.9.4092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tennant R. W., Farrelly J. G., Ihle J. N., Pal B. C., Kenney F. T., Brown A. Effects of polyadenylic acids on functions of murine RNA tumor viruses. J Virol. 1973 Dec;12(6):1216–1225. doi: 10.1128/jvi.12.6.1216-1225.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Thang M. N., Bachner L., De Clercq E., Stollar B. D. A continuous high molecular weight base-paired structure is not an absolute requirement for a potential polynucleotide inducer of interferon. FEBS Lett. 1977 Apr 15;76(2):159–165. doi: 10.1016/0014-5793(77)80143-9. [DOI] [PubMed] [Google Scholar]
  26. Thang M. N., De Maeyer-Guignard J., De Maeyer E. Interaction of interferon with tRNA. FEBS Lett. 1977 Aug 15;80(2):365–370. doi: 10.1016/0014-5793(77)80477-8. [DOI] [PubMed] [Google Scholar]
  27. Thiele D., Guschlbauer W. The structures of polyinosinic acid. Biophysik. 1973 May 30;9(3):261–277. doi: 10.1007/BF01184691. [DOI] [PubMed] [Google Scholar]
  28. Torrence P. F., De Clercq E., Waters J. A., Witkop B. A potent interferon inducer derived from poly (7-deazainosinic acid). Biochemistry. 1974 Oct 8;13(21):4400–4408. doi: 10.1021/bi00718a025. [DOI] [PubMed] [Google Scholar]
  29. Torrence P. F., De Clercq E., Waters J. A., Witkop B. Failure of duplexes based on polylaurusin (poly(L), "Polyformycin B") to induce interferon. Biochem Biophys Res Commun. 1975 Feb 3;62(3):658–664. doi: 10.1016/0006-291x(75)90449-0. [DOI] [PubMed] [Google Scholar]
  30. Uesugi S., Yano J., Yano E., Ikehara M. Synthesis and properties of the dinucleoside monophosphates containing adenine S-cyclonucleosides and adenosine. Factors determining the stability and handedness of the stacking conformation in a dinucleoside monophosphate. J Am Chem Soc. 1977 Mar 30;99(7):2313–2323. doi: 10.1021/ja00449a049. [DOI] [PubMed] [Google Scholar]
  31. Uesugi S., Yasumoto M., Ikehara M., Fang K. N., Ts'o P. O. Synthesis and properties of the dinucleoside monophosphate of adenine 8-thiocyclonucleoside. J Am Chem Soc. 1972 Jul 26;94(15):5480–5486. doi: 10.1021/ja00770a053. [DOI] [PubMed] [Google Scholar]
  32. Ward D. C., Reich E. Conformational properties of polyformycin: a polyribonucleotide with individual residues in the syn conformation. Proc Natl Acad Sci U S A. 1968 Dec;61(4):1494–1501. doi: 10.1073/pnas.61.4.1494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. de Clercq E., Torrence P. F., Stollar B. D., Hobbs J., Fukui T., Kakiuchi N., Ikehara M. Interferon induction by a 2'-modified double-helical RNA, poly(2'-azido-2'-deoxyinosinic acid) . polycytidylic acid. Eur J Biochem. 1978 Aug 1;88(2):341–349. doi: 10.1111/j.1432-1033.1978.tb12455.x. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES