DOI QR코드

DOI QR Code

A Novel Chemical Compound for Inhibition of SARS Coronavirus Helicase

  • Lee, Jin-Moo (Department of Applied Chemistry, Kookmin University) ;
  • Cho, Jin-Beom (Department of Applied Chemistry, Kookmin University) ;
  • Ahn, Hee-Chul (Department of Pharmacy, Dongguk University-Seoul) ;
  • Jung, Woong (Department of Emergency Medicine, Kyung Hee University Hospital at Gangdong) ;
  • Jeong, Yong-Joo (Department of Applied Chemistry, Kookmin University)
  • Received : 2017.07.31
  • Accepted : 2017.09.05
  • Published : 2017.11.28

Abstract

We have discovered a novel chemical compound, (E)-3-(furan-2-yl)-N-(4-sulfamoylphenyl) acrylamide, that suppresses the enzymatic activities of SARS coronavirus helicase. To determine the inhibitory effect, ATP hydrolysis and double-stranded DNA unwinding assays were performed in the presence of various concentrations of the compound. Through these assays, we obtained $IC_{50}$ values of $2.09{\pm}0.30{\mu}M$ (ATP hydrolysis) and $13.2{\pm}0.9{\mu}M$ (DNA unwinding), respectively. Moreover, we found that the compound did not have any significant cytotoxicity when $40{\mu}M$ of it was used. Our results showed that the compound might be useful to be developed as an inhibitor against SARS coronavirus.

Keywords

References

  1. Marra MA, Jones SJ, Astell CR, Holt RA, Brooks-Wilson A, Butterfield YS, et al. 2003. The genome sequence of the SARS-associated coronavirus. Science 300: 1399-1404. https://doi.org/10.1126/science.1085953
  2. Rota PA, Oberste MS, Monroe SS, Nix WA, Campagnoli R, Icenogle JP, et al. 2003. Characterization of a novel coronavirus associated with severe acute respiratory syndrome. Science 300: 1394-1399. https://doi.org/10.1126/science.1085952
  3. Lai MM, Cavanagh D. 1997. The molecular biology of coronaviruses. Adv. Virus Res. 48: 1-100.
  4. Ziebuhr J, Snijder EJ, Gorbalenya AE. 2000. Virus-encoded proteinases and proteolytic processing in the Nidovirales. J. Gen. Virol. 81: 853-879. https://doi.org/10.1099/0022-1317-81-4-853
  5. Ivanov KA, Thiel V, Dobbe JC, van der Meer Y, Snijder EJ, Ziebuhr J. 2004. Multiple enzymatic activities associated with severe acute respiratory syndrome coronavirus helicase. J. Virol. 78: 5619-5632. https://doi.org/10.1128/JVI.78.11.5619-5632.2004
  6. Tanner JA, Watt RM, Chai YB, Lu LY, Lin MC, Peiris JS, et al. 2003. The severe acute respiratory syndrome (SARS) coronavirus NTPase/helicase belongs to a distinct class of 5' to 3' viral helicases. J. Biol. Chem. 278: 39578-39582. https://doi.org/10.1074/jbc.C300328200
  7. Anand K, Ziebuhr J, Wadhwani P, Mesters JR, Hilgenfeld R. 2003. Coronavirus main proteinase (3CLpro) structure: basis for design of anti-SARS drugs. Science 300: 1763-1767. https://doi.org/10.1126/science.1085658
  8. Borowski P, Schalinski S, Schmitz H. 2002. Nucleotide triphosphatase/helicase of hepatitis C virus as a target for antiviral therapy. Antiviral Res. 55: 397-412. https://doi.org/10.1016/S0166-3542(02)00096-7
  9. Holmes KV. 2003. SARS coronavirus: a new challenge for prevention and therapy. J. Clin. Invest. 111: 1605-1609. https://doi.org/10.1172/JCI18819
  10. Patel SS, Donmez I. 2006. Mechanisms of helicases. J. Biol. Chem. 281: 18265-18268. https://doi.org/10.1074/jbc.R600008200
  11. Patel SS, Picha KM. 2000. Structure and function of hexameric helicases. Annu. Rev. Biochem. 69: 651-697. https://doi.org/10.1146/annurev.biochem.69.1.651
  12. Matson SW, Bean DW, George JW. 1994. DNA helicases:enzymes with essential roles in all aspects of DNA metabolism. Bioessays 16: 13-22. https://doi.org/10.1002/bies.950160103
  13. Lee C, Lee JM, Lee NR, Jin BS, Jang KJ, Kim DE, et al. 2009. Aryl diketoacids (ADK) selectively inhibit duplex DNAunwinding activity of SARS coronavirus NTPase/helicase. Bioorg. Med. Chem. Lett. 19: 1636-1638. https://doi.org/10.1016/j.bmcl.2009.02.010
  14. Lee NR, Kwon HM, Park K, Oh S, Jeong YJ, Kim DE. 2010. Cooperative translocation enhances the unwinding of duplex DNA by SARS coronavirus helicase nsP13. Nucleic Acids Res. 38: 7626-7636. https://doi.org/10.1093/nar/gkq647
  15. Lee NR, Lee AR, Lee B, Kim D-E, Jeong YJ. 2009. ATP hydrolysis analysis of severe acute respiratory syndrome (SARS) coronavirus helicase. Bull. Korean Chem. Soc. 30:1724-1728. https://doi.org/10.5012/bkcs.2009.30.8.1724
  16. Lee C, Lee JM, Lee NR, Kim DE, Jeong YJ, Chong Y. 2009. Investigation of the pharmacophore space of severe acute respiratory syndrome coronavirus (SARS-CoV) NTPase/helicase by dihydroxychromone derivatives. Bioorg. Med. Chem. Lett. 19: 4538-4541. https://doi.org/10.1016/j.bmcl.2009.07.009
  17. Yu MS, Lee J, Lee JM, Kim Y, Chin YW, Jee JG, et al. 2012. Identification of myricetin and scutellarein as novel chemical inhibitors of the SARS coronavirus helicase, nsP13. Bioorg. Med. Chem. Lett. 22: 4049-4054. https://doi.org/10.1016/j.bmcl.2012.04.081
  18. Jang KJ, Lee NR, Yeo WS, Jeong YJ, Kim DE. 2008. Isolation of inhibitory RNA aptamers against severe acute respiratory syndrome (SARS) coronavirus NTPase/helicase. Biochem. Biophys. Res. Commun. 366: 738-744. https://doi.org/10.1016/j.bbrc.2007.12.020
  19. Cho JB, Lee JM, Ahn HC, Jeong YJ. 2015. Identification of a novel small molecule inhibitor against SARS coronavirus helicase. J. Microbiol. Biotechnol. 25: 2007-2010. https://doi.org/10.4014/jmb.1507.07078

Cited by

  1. Hepatitis E Virus Methyltransferase Inhibits Type I Interferon Induction by Targeting RIG-I vol.28, pp.9, 2017, https://doi.org/10.4014/jmb.1808.08058
  2. Hepatitis E Virus Papain-Like Cysteine Protease Inhibits Type I Interferon Induction by Down-Regulating Melanoma Differentiation-Associated Gene 5 vol.28, pp.11, 2017, https://doi.org/10.4014/jmb.1809.09028
  3. Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations vol.13, pp.10, 2017, https://doi.org/10.3390/ph13100277
  4. Chinese Therapeutic Strategy for Fighting COVID-19 and Potential Small-Molecule Inhibitors against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vol.63, pp.22, 2017, https://doi.org/10.1021/acs.jmedchem.0c00626
  5. A high ATP concentration enhances the cooperative translocation of the SARS coronavirus helicase nsP13 in the unwinding of duplex RNA vol.10, pp.None, 2017, https://doi.org/10.1038/s41598-020-61432-1
  6. A multi-pronged approach targeting SARS-CoV-2 proteins using ultra-large virtual screening vol.24, pp.2, 2017, https://doi.org/10.1016/j.isci.2020.102021
  7. Structure-Based Virtual Screening Identifies Multiple Stable Binding Sites at the RecA Domains of SARS-CoV-2 Helicase Enzyme vol.26, pp.5, 2017, https://doi.org/10.3390/molecules26051446
  8. Coronavirus helicases: attractive and unique targets of antiviral drug-development and therapeutic patents vol.31, pp.4, 2017, https://doi.org/10.1080/13543776.2021.1884224
  9. Human endeavor for anti-SARS-CoV-2 pharmacotherapy: A major strategy to fight the pandemic vol.137, pp.None, 2021, https://doi.org/10.1016/j.biopha.2021.111232
  10. Main Chemotypes of SARS-CoV-2 Reproduction Inhibitors vol.57, pp.5, 2017, https://doi.org/10.1134/s107042802105002x
  11. Single-molecule kinetic locking allows fluorescence-free quantification of protein/nucleic-acid binding vol.4, pp.1, 2017, https://doi.org/10.1038/s42003-021-02606-z