Genetic Engineering in Combination with Semi-Synthesis Leads to a New Route for Gram-Scale Production of the Immunosuppressive Natural Product Brasilicardin A

Angew Chem Int Ed Engl. 2021 Jun 7;60(24):13536-13541. doi: 10.1002/anie.202015852. Epub 2021 May 1.

Abstract

Brasilicardin A (1) consists of an unusual anti/syn/anti-perhydrophenanthrene skeleton with a carbohydrate side chain and an amino acid moiety. It exhibits potent immunosuppressive activity, yet its mode of action differs from standard drugs that are currently in use. Further pre-clinical evaluation of this promising, biologically active natural product is hampered by restricted access to the ready material, as its synthesis requires both a low-yielding fermentation process using a pathogenic organism and an elaborate, multi-step total synthesis. Our semi-synthetic approach included a) the heterologous expression of the brasilicardin A gene cluster in different non-pathogenic bacterial strains producing brasilicardin A aglycone (5) in excellent yield and b) the chemical transformation of the aglycone 5 into the trifluoroacetic acid salt of brasilicardin A (1 a) via a short and straightforward five-steps synthetic route. Additionally, we report the first preclinical data for brasilicardin A.

Keywords: brasilicardin A; heterologous expression; natural products; semi-synthesis; terpenoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / genetics
  • Aminoglycosides / chemical synthesis
  • Aminoglycosides / chemistry
  • Aminoglycosides / metabolism*
  • Aminoglycosides / pharmacology
  • Animals
  • Biological Products / chemical synthesis
  • Biological Products / chemistry
  • Biological Products / metabolism
  • Biological Products / pharmacology
  • Cell Line
  • Cell Survival / drug effects
  • Genetic Engineering*
  • Humans
  • Immunosuppressive Agents / chemical synthesis*
  • Immunosuppressive Agents / chemistry
  • Immunosuppressive Agents / metabolism
  • Immunosuppressive Agents / pharmacology
  • Mice
  • Plasmids / genetics
  • Plasmids / metabolism
  • Streptomyces / genetics
  • Streptomyces / metabolism
  • Terpenes / chemistry

Substances

  • Aminoglycosides
  • Biological Products
  • Immunosuppressive Agents
  • Terpenes
  • brasilicardin A
  • Alkyl and Aryl Transferases