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Sandacrabins – Structurally Unique Antiviral RNA Polymerase Inhibitors from a Rare Myxobacterium **
Author(s) -
Bader Chantal D.,
Panter Fabian,
Garcia Ronald,
Tchesnokov Egor P.,
Haid Sibylle,
Walt Christine,
Spröer Cathrin,
Kiefer Alexander F.,
Götte Matthias,
Overmann Jörg,
Pietschmann Thomas,
Müller Rolf
Publication year - 2022
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202104484
Subject(s) - rna , polymerase , enzyme , rna polymerase , biology , biochemistry , rna dependent rna polymerase , genome , chemistry , nucleoside , computational biology , gene
Structure elucidation and total synthesis of five unprecedented terpenoid‐alkaloids, the sandacrabins, are reported, alongside with the first description of their producing organism Sandaracinus defensii MSr10575, which expands the Sandaracineae family by only its second member. The genome sequence of S. defensii as presented in this study was utilized to identify enzymes responsible for sandacrabin formation, whereby dimethylbenzimidazol, deriving from cobalamin biosynthesis, was identified as key intermediate. Biological activity profiling revealed that all sandacrabins except congener A exhibit potent antiviral activity against the human pathogenic coronavirus HCoV229E in the three digit nanomolar range. Investigation of the underlying mode of action discloses that the sandacrabins inhibit the SARS‐CoV‐2 RNA‐dependent RNA polymerase complex, highlighting them as structurally distinct non‐nucleoside RNA synthesis inhibitors. The observed segregation between cell toxicity at higher concentrations and viral inhibition opens the possibility for their medicinal chemistry optimization towards selective inhibitors.