Pharmacology
Bacterial iron-chelating pigments called ferroverdins turn out to be potent CETP inhibitors, with 43 new structural variants identified (Biomolecules 2022)
Original title: Structure of New Ferroverdins Recruiting Unconventional Ferrous Iron Chelating Agents
Ferroverdins are ferrous-iron nitrosophenolate complexes made by some Streptomyces bacteria in response to iron overload; three had previously been identified, ferroverdin A, B and C, differing in the ligands they use to bind iron. Ferroverdin B, and by extension the class, had shown potent inhibition of human CETP, making these natural products candidate leads for HDL-raising cardiovascular drugs. Using high-resolution tandem mass spectrometry on two Streptomyces lunaelactis species, the authors identified 43 novel ferroverdins, fully elucidating the structure of 13 of them (named C2, C3, D, D2, D3, E, F, G, H, CD, DE, DF and DG) and partially resolving 17 more. Five new iron-chelating ligand chemistries were identified, and two compounds (C3 and D3) were the first ferroverdins found not to use the originally described core ligand. The work expands the pool of candidate CETP inhibitors from this natural product family, a structural chemistry discovery paper without CETP inhibition assay data on the new compounds themselves.
Original abstract
Ferroverdins are ferrous iron (Fe2+)-nitrosophenolato complexes produced by a few Streptomyces species as a response to iron overload. Previously, three ferroverdins were identified: ferroverdin A, in which three molecules of p-vinylphenyl-3-nitroso-4-hydroxybenzoate (p-vinylphenyl-3,4-NHBA) are recruited to bind Fe2+, and Ferroverdin B and Ferroverdin C, in which one molecule of p-vinylphenyl-3,4-NHBA is substituted by hydroxy-p-vinylphenyl-3,4-NHBA, and by carboxy-p-vinylphenyl-3,4-NHBA, respectively. These molecules, especially ferroverdin B, are potent inhibitors of the human cholesteryl ester transfer protein (CETP) and therefore candidate hits for the development of drugs that increase the serum concentration of high-density lipoprotein cholesterol, thereby diminishing the risk of atherosclerotic cardiovascular disease. In this work, we used high-resolution mass spectrometry combined with tandem mass spectrometry to identify 43 novel ferroverdins from the cytosol of two Streptomyces lunaelactis species. For 13 of them (designated ferroverdins C2, C3, D, D2, D3, E, F, G, H, CD, DE, DF, and DG), we could elucidate their structure, and for the other 17 new ferroverdins, ambiguity remains for one of the three ligands. p-formylphenyl-3,4-NHBA, p-benzoic acid-3,4-NHBA, 3,4-NHBA, p-phenylpropionate-3,4-NHBA, and p-phenyacetate-3,4-NHBA were identified as new alternative chelators for Fe2+-binding, and two compounds (C3 and D3) are the first reported ferroverdins that do not recruit p-vinylphenyl-3,4-NHBA. Our work thus uncovered putative novel CETP inhibitors or ferroverdins with novel bioactivities.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.