Dihydromaniwamycin E, a Heat-Shock Metabolite from Thermotolerant <i>Streptomyces</i> sp. JA74, Exhibiting Antiviral Activity against Influenza and SARS-CoV-2 Viruses.
Saito S, Funayama K, Kato W, Okuda M, Kawamoto M, Matsubara T, Sato T, Sato A, Otsuguro S, Sasaki M, Orba Y, Sawa H, Maenaka K, Shindo K, Imoto M, Arai MA.
Dihydromaniwamycin E (<b>1</b>), a new maniwamycin derivative featuring an azoxy moiety, has been isolated from the culture extract of thermotolerant <i>Streptomyces</i> sp. JA74 along with the known analogue maniwamycin E (<b>2</b>). Compound <b>1</b> 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 <b>2</b> is detected as a production-enhanced metabolite at high temperature. Structures of <b>1</b> and <b>2</b> are elucidated by NMR and MS spectroscopic analyses. The absolute structure of <b>1</b> is determined after the total synthesis of four stereoisomers. Though the absolute structure of <b>2</b> has been proposed to be the same as the structure of maniwamycin D, the NMR and the optical rotation value of <b>2</b> are in agreement with those of maniwamycin E. Therefore, this study proposes a structural revision of maniwamycins D and E. Compounds <b>1</b> and <b>2</b> show inhibitory activity against the influenza (H1N1) virus infection of MDCK cells, demonstrating IC<sub>50</sub> values of 25.7 and 63.2 μM, respectively. Notably, <b>1</b> and <b>2</b> display antiviral activity against SARS-CoV-2, the causative agent of COVID-19, when used to infect 293TA and VeroE6T cells, with <b>1</b> and <b>2</b> showing IC<sub>50</sub> 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 IC<sub>50</sub> concentrations.