Biological and Medicinal Chemistry

Sandacrabins – Structurally unique antiviral RNA polymerase inhibitors from a rare myxobacterium

Authors

  • Chantal Bader Helmholtz Institute for Pharmaceutical Research Saarland & Universität des Saarlandes - Germany & Helmholtz Centre for Infection Research ,
  • Fabian Panter Helmholtz Institute for Pharmaceutical Research Saarland & Universität des Saarlandes - Germany & Helmholtz Centre for Infection Research ,
  • Ronald Garcia Helmholtz Institute for Pharmaceutical Research Saarland & Universität des Saarlandes - Germany & Helmholtz Centre for Infection Research ,
  • Egor Tchesnokov University of Alberta ,
  • Sibylle Haid Institute of Experimental Virology Twincore - Germany ,
  • Christine Walt Helmholtz Institute for Pharmaceutical Research Saarland & Universität des Saarlandes - Germany & Helmholtz Centre for Infection Research ,
  • Cathrin Spröer Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures ,
  • Alexander Kiefer Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research ,
  • Matthias Götte University of Alberta ,
  • Jörg Overmann Leibniz Institute DSMZ – German Collection of Microorganisms and Cell Cultures ,
  • Thomas Pietschmann Institute of Experimental Virology Twincore - Germany ,
  • Rolf Müller Helmholtz Institute for Pharmaceutical Research Saarland & Helmholtz Centre for Infection Research & Universität des Saarlandes - Germany

Abstract

We report structure elucidation and total synthesis of five unprecedented terpenoid-alkaloids, the sandacrabins, 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 represents a good starting point for their medicinal chemistry optimization towards selective inhibitors.

Content

Thumbnail image of 2021-10-14_Sandacrabins_Clean.pdf

Supplementary material

Thumbnail image of 2021-10-14_Sandacrabine_SI.pdf
Supporting Information
In the supporting information we describe the microbiological and analytical methodology used for the preparation, analysis and purification of the bacterial extracts. We also report the strains morphology and genome analysis, as well as NMR raw data and details regarding the synthesis procedures, as well as about the biological assays. The Sandaracinus defensii genome sequence was deposited in GenBank.