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

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

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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