Dihydromaniwamycin E, a Heat-Shock Metabolite from Thermotolerant Streptomyces sp. JA74, Exhibiting Antiviral Activity against Influenza and SARS-CoV-2 Viruses

  • J Nat Prod. 2022 Oct 12;acs.jnatprod.2c00550. doi: 10.1021/acs.jnatprod.2c00550.
Shun Saito  1 ,  Kayo Funayama  1 ,  Wataru Kato  1 ,  Mayu Okuda  1 ,  Meiko Kawamoto  1 ,  Teruhiko Matsubara  1 ,  Toshinori Sato  1 ,  Akihiko Sato  2  3 ,  Satoko Otsuguro  4 ,  Michihito Sasaki  3 ,  Yasuko Orba  3  5 ,  Hirofumi Sawa  3  5  6  7 ,  Katsumi Maenaka  4 ,  Kazutoshi Shindo  8 ,  Masaya Imoto  9 ,  Midori A Arai  1
Affiliations
  • 1. Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama223-8522, Japan.
  • 2. Drug Discovery and Disease Research Laboratory, Shionogi & Co., Ltd., Osaka541-0045, Japan.
  • 3. Division of Molecular Pathobiology, International Institute for Zoonosis Control, Hokkaido University, Sapporo001-0020, Japan.
  • 4. Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo060-0812, Japan.
  • 5. International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo001-0020, Japan.
  • 6. One Health Research Center, Hokkaido University, Sapporo060-0818, Japan.
  • 7. Global Virus Network, Baltimore, Maryland21201, United States.
  • 8. Department of Food and Nutrition, Japan Women's University, Tokyo112-8681, Japan.
  • 9. Department of Neurology, Juntendo University School of Medicine, Tokyo113-8431, Japan.
PMID: 36223390 DOI: 10.1021/acs.jnatprod.2c00550
Abstract

Dihydromaniwamycin E (1), a new maniwamycin derivative featuring an azoxy moiety, has been isolated from the culture extract of thermotolerant Streptomyces sp. JA74 along with the known analogue maniwamycin E (2). Compound 1 is produced only by cultivation of strain JA74 at 45 °C, and this type of compound has been previously designated a "heat shock metabolite (HSM)" by our research group. Compound 2 is detected as a production-enhanced metabolite at high temperature. Structures of 1 and 2 are elucidated by NMR and MS spectroscopic analyses. The absolute structure of 1 is determined after the total synthesis of four stereoisomers. Though the absolute structure of 2 has been proposed to be the same as the structure of maniwamycin D, the NMR and the optical rotation value of 2 are in agreement with those of maniwamycin E. Therefore, this study proposes a structural revision of maniwamycins D and E. Compounds 1 and 2 show inhibitory activity against the influenza (H1N1) virus Infection of MDCK cells, demonstrating IC50 values of 25.7 and 63.2 μM, respectively. Notably, 1 and 2 display Antiviral activity against SARS-CoV-2, the causative agent of COVID-19, when used to infect 293TA and VeroE6T cells, with 1 and 2 showing IC50 values (for Infection of 293TA cells) of 19.7 and 9.7 μM, respectively. The two compounds do not exhibit cytotoxicity in these cell lines at those IC50 concentrations.

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