Cycloferon as a Means for Prevention, Treatment, and Control of COVID-19: Multidisciplinary and Comparative Historical Aspects

The study of coronaviruses, including those capable of causing life-threatening diseases, continued for many decades. So did the study of interferons, as well as acridine acetic acid, which is a powerful interferon inducer. For a long time, both directions of research developed in parallel to each other. However, the discovery of SARS-CoV and the creation of Cycloferon based on acridine acetic acid made both research directions converge. To date, the abundance of factual and theoretical tenets is enough to estimate the potential effectiveness of acridine acetic acid against COVID-19. 

1. Fung S.Y., Yuen K.S., Ye Z.W., Chan C.P. et al. A tug-of-war between severe acute respiratory syndrome coronavirus 2 and host antiviral defence: lessons from other pathogenic viruses. Emerg Microbes Infect. 2020 Mar 14; 9 (1): 558–570. doi:10.1080/22221751.2020.1736644. eCollection 2020.

2. Kendall E.J., Bynoe M.L., Tyrrell D.A. Virus isolations from common colds occurring in a residential school. Br Med J. 1962; 2: 82–86. doi:10.1136/bmj.2.5297.82.

3. Kovalenko A. L., Grigoryan S. S., Romantsov M. G., Petrov A. Yu. i dr. Interferoninduktivnaya aktivnost' i produktsiya interferonov pod vliyaniem solej akridonuksusnoj kisloty. Eksperimental'naya i Klinicheskaya Farmakologiya. 2014; 77 (11): 16–19. (in Russian)

4. Szulc B., Inglot A.D., Szulc Z., Młochowski J. Competition of sodium salt of 9-oxo-10-acridineacetic acid with analogs during induction of interferon in the mouse bone marrow-derived macrophages. Arch Immunol Ther Exp (Warsz). 1985; 33 (2): 287–97.

5. Taylor J.L., Schoenherr C.K., Grossberg S.E. High-yield interferon induction by 10-carboxymethyl-9-acridanone in mice and hamsters. Antimicrob Agents Chemother. 1980 Jul; 18 (1): 20–26.

6. Vremennye metodicheskie rekomendatsii. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infektsii (COVID-19). Versiya 15 (22.02.2022). Ministerstvo Zdravookhraneniya RF. 2021; 245. (in Russian)

7. Mazin P.V., Khafiz'yanova R.Kh., Mazina N.K., Kovalenko A.L. i dr. Meglyumin akridonatsetat protiv COVID-19: perspektivy ispol'zovaniya. Infektsionnye Bolezni. 2020; 18 (4): 42–52. (in Russian)

8. Basharina A. K. Ponyatie «semanticheskoe pole». Vestnik Severo-Vostochnogo Federal'nogo Universiteta im. M. K. Ammosova. 2007; 4 (1): 93–96. (in Russian)

9. Smirnov A.A. Primenenie nechetkoj logiki pri formirovanii znanij. Innovatsionnaya Nauka. 2016; 3: 184–186. (in Russian)

10. McIntosh K. Coronaviruses: a comparative review. Curr Top Microbiol Immunol. 1974; 63: 85–129.

11. Isaacs A., Lindenmann J. Virus interference. I. The interferon. Proc R Soc Lond B Biol Sci 1957; 147: 258–267.

12. Isaacs A., Lindenmann J., Valentine R.C. Virus interference. II. Some properties of interferon. Proc R Soc Lond Biol Sci. 1957; 147 (927): 268–273.

13. Brehm G., Storch E., Kirchner H. Characterization of Interferon Induced in Murine Macrophage Cultures by 10-carboxymethyl-9-acridanone. Nat Immun Cell Growth Regul. 1986; 5(1): 50–9.

14. Storch E., Kirchner H. Induction of Interferon in Murine Bone MarrowDerived Macrophage Cultures by 10-carboxymethyl-9-acridanone. Eur J Immunol. 1982 Sept; 12 (9): 793–796. doi:10.1002/eji.1830120918.

15. Storch E., Kirchner H., Brehm G., Hüller K. et al. Production of Interferon-Beta by Murine T-cell Lines Induced by 10-carboxymethyl-9-acridanone. Scand J Immunol. 1986 Feb; 23 (2): 195–199. doi:10.1111/j.1365-3083.1986.tb01958.x.

16. Storch E., Kirchner H., Hüller K., Martinotti M.G. et al. Enhancement by carprofen or indomethacin of interferon induction by 10-carboxymethyl9-acridanone in murine cell cultures. J Gen Virol. 1986 Jun; 67 ( Pt 6): 1211–1214. doi:10.1099/0022-1317-67-6-1211.

17. Kramer M. J., Cleeland R., Grunberg E. Antiviral activity of 10-carboxymethyl-9-acridanone. Antimicrob Agents Chemother. 1976; 9(2): 233–238. doi:10.1128/AAC.9.2.233.

18. Inglot A.D., Młochowski J., Szulc Z., Inglot O., Albin M. Induction of interferon in mice by sodium salt of 9-oxo-10-acridineacetic acid: specific enhancement by analogs. Arch Immunol Ther Exp (Warsz). 1985; 33 (2): 275–285.

19. Taylor J.L., Schoenherr C., Grossberg S.E. Protection against Japanese encephalitis virus in mice and hamsters by treatment with carboxymethylacridanone, a potent interferon inducer. J Infect Dis. 1980 Sep; 142 (3): 394–399.

20. Szulc B., Inglot A.D., Inglot O. Tolerance or hyperreactivity to interferon induction by sodium salt of 9-oxo-10-acridineacetic acid and analogs in mice and in the mouse macrophage cultures. Arch Immunol Ther Exp (Warsz). 1987; 35 (3): 389–395.

21. Baltimore D. Expression of animal virus genomes. Microbiology and Molecular Biology Reviews. American Society for Microbiology, 1971; 35 (3): 235–241.

22. https://talk.ictvonline.org/taxonomy

23. Pashchenkov M.V., Khaitov M.R. Immunnyj otvet protiv epidemicheskikh koronavirusov. Immunologiya. 2020, 41 (1): 5–18. (in Russian)

24. Agaeva S. G. Vliyanie protivovirusnoj terapii na techenie khronicheskogo gepatita V u detej. Detskie Infektsii. 2004; 1: 33–35. (in Russian)

25. Ershov F.I., Kiselev O.I. Interferony i ikh induktory (ot molekul do lekarstv). Moscow: 2005. (in Russian)

26. Zarubaev V. V., Sukhinin V. P., Slita A. V., Sirotkin A. K. Vliyanie tsikloferona na morfogenez i reproduktsiyu virusa prostogo gerpesa 1 tipa v kul'ture kletok vero. Vestnik Sankt-Peterburgskoj Gosudarstvennoj Meditsinskoj Akademii im. I. M. Mechnikova. 2003; 4 (4): 152–156. (in Russian)

27. Sukhinin V. P., Pleskov V.M., Zarubaev V.V., Slita A. V. Ispol'zovanie tsikloferona v terapii eksperimental'nogo gerpeticheskogo keratita. Antibiotiki i Khimioter = Antibiotics and Chemotherapy. 2000; 45 (6): 13–16. (in Russian)

28. Yuan H., You J., You H., Zheng C. Herpes Simplex Virus 1 UL36USP Antagonizes Type I Interferon-Mediated Antiviral Innate Immunity. J Virol. 2018; 92 (19): e01161–18. doi:10.1128/JVI.01161-18.

29. Huang J., You H., Su C., Li Y. et al. Herpes Simplex Virus 1 Tegument Protein VP22 Abrogates cGAS/STING-Mediated Antiviral Innate Immunity. J Virol. 2018; 92 (15): e00841-18. doi:10.1128/JVI.00841-18.

30. Sato Y., Koshizuka T., Ishibashi K., Hashimoto K. et al. Involvement of herpes simplex virus type 1 UL13 protein kinase in induction of SOCS genes, the negative regulators of cytokine signaling. Microbiol Immunol. 2017; 61 (5): 159–167. doi:10.1111/1348-0421.12483.

31. Pan S., Liu X., Ma Y., Cao Y. et al. Herpes Simplex Virus 1 γ134.5 Protein Inhibits STING Activation That Restricts Viral Replication. J Virol. 2018; 92 (20): e01015-18. doi:10.1128/JVI.01015-18. Print 2018 Oct 15.

32. Hong Y., Zhou L., Xie H., Zheng S. Innate immune evasion by hepatitis B virus-mediated downregulation of TRIF. Biochem Biophys Res Commun. 2015 Aug 7; 463 (4): 719–725. doi:10.1016/j.bbrc.2015.05.130.

33. Qu L., Lemon S.M. Hepatitis A and hepatitis C viruses: divergent infection outcomes marked by similarities in induction and evasion of interferon responses. Semin Liver Dis. 2010 Nov; 30 (4): 319–332. doi:10.1055/s0030-1267534.

34. Colpitts C.C., Ridewood S., Schneiderman B., Warne J., Tabata K., Ng C.F., Bartenschlager R., Selwood D.L., Towers G.J. Hepatitis C virus exploits cyclophilin A to evade PKR. Elife. 2020 Jun 16; 9: e52237. doi:10.7554/eLife.52237.

35. Liu S., Peng N., Xie J., Hao Q. et al. Human hepatitis B virus surface and e antigens inhibit major vault protein signaling in interferon induction pathways. J Hepatol. 2015 May; 62 (5): 1015–1023. doi:10.1016/j.jhep.2014.11.035. Epub 2014 Dec 3.

36. Vincent I.E., Zannetti C., Lucifora J., Norder H. et al. Hepatitis B virus impairs TLR9 expression and function in plasmacytoid dendritic cells. PLoS One. 2011; 6 (10): e26315. doi:10.1371/journal.pone.0026315. Epub 2011 Oct 25.

37. Felgenhauer U., Schoen A., Gad H.H., Hartmann R. et al. Inhibition of SARS-CoV-2 by type I and type III interferons. J Biol Chem. 2020 Oct 9; 295 (41): 13958–13964. doi:10.1074/jbc.AC120.013788. Epub 2020 Jun 25.

38. O'Brien T.R., Thomas D.L., Jackson S.S., Prokunina-Olsson L. et al. Weak Induction of Interferon Expression by SARS-CoV-2 Supports Clinical Trials of Interferon Lambda to Treat Early COVID-19. Clin Infect Dis. 2020; 71 (6): 1410–1412. doi:10.1093/cid/ciaa453.

39. Prokunina-Olsson L., Alphonse N., Dickenson R.E., Durbin J.E. et al. COVID-19 and emerging viral infections: The case for interferon lambda. J Exp Med. 2020 May 4; 217 (5): e20200653. doi:10.1084/jem.20200653.

40. Chung J.H., Hong S.H., Seo N., Kim T.S. et al. Structure-based glycoengineering of interferon lambda 4 enhances its productivity and anti-viral potency. Cytokine. 2020 Jan; 125: 154833. doi:10.1016/j.cyto.2019.154833. Epub 2019 Aug 31.

41. Feng L., Sheng J., Vu G.P., Liu Y. et al. Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein. PLoS Pathog. 2018, 14 (1): e1006867. doi:10.1371/journal.ppat.1006867. eCollection 2018 Jan.

42. Marques M., Ferreira A.R., Ribeiro D. The Interplay between Human Cytomegalovirus and Pathogen Recognition Receptor Signaling. Viruses. 2018; 10 (10): E 514. doi:10.3390/v10100514.

43. Mezentsev M.V., Agrba V.Z., Karal-ogly D.D., Agumava A.A. Tsikloferon v terapii tsitomegalovirusnoj infektsii obez'yan. Eksperimental'naya i Klinicheskaya Farmakologiya. 2012; 75 (12): 37–40. (in Russian)

44. de Weerd N.A., Nguyen T. The interferons and their receptors—distribution and regulation. Immunology and Cell Biology. 2012; 90 (5): 483–491. doi:10.1038/icb.2012.9. Epub 2012 Mar 13.

45. Ioannidi E. A., Chernyavskaya O.A., Bozhko V.G. Opyt primeneniya tsikloferona v lechenii likhoradki Zapadnogo Nila. Volgogradskij Nauchno-Meditsinskij Zhurnal. 2013; 4: 38–42. (in Russian)

46. Vremennye metodicheskie rekomendatsii. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infektsii (COVID-19). Versiya 7 (03.06.2020). Ministerstvo zdravookhraneniya RF, 2020; 166.

47. Vremennye metodicheskie rekomendatsii. Profilaktika, diagnostika i lechenie novoj koronavirusnoj infektsii (COVID-19). Versiya 13 (14.10.2021). Ministerstvo Zdravookhraneniya RF. 2021; 237. (in Russian)

48. Plotnikova M.A., Klotchenko S.A., Kiselev A.A., Gorshkov A.N. et al. Meglumine acridone acetate, the ionic salt of CMA and N-methylglucamine, induces apoptosis in human PBMCs via the mitochondrial pathway. Sci Rep. 2019 Dec 3; 9 (1): 18240. doi:10.1038/s41598-019-54208-9.