Native metabolomics identifies the rivulariapeptolide family of protease inhibitors.
Raphael ReherAllegra T AronPavla FajtováPaolo StinconeBerenike WagnerAlicia I Pérez-LorenteChenxi LiuIdo Y Ben ShalomWout BittremieuxMingxun WangKyowon JeongMarie L Matos-HernandezKelsey L AlexanderEduardo J Caro-DiazC Benjamin NamanJ H William ScanlanPhil M M HochbanWibke E DiederichCarlos Molina-SantiagoDiego RomeroKhaled A SelimPeter SassHeike Brötz-OesterheltChambers C HughesPieter C DorresteinAnthony J O'DonoghueWilliam H GerwickDaniel PetrasPublished in: Nature communications (2022)
The identity and biological activity of most metabolites still remain unknown. A bottleneck in the exploration of metabolite structures and pharmaceutical activities is the compound purification needed for bioactivity assignments and downstream structure elucidation. To enable bioactivity-focused compound identification from complex mixtures, we develop a scalable native metabolomics approach that integrates non-targeted liquid chromatography tandem mass spectrometry and detection of protein binding via native mass spectrometry. A native metabolomics screen for protease inhibitors from an environmental cyanobacteria community reveals 30 chymotrypsin-binding cyclodepsipeptides. Guided by the native metabolomics results, we select and purify five of these compounds for full structure elucidation via tandem mass spectrometry, chemical derivatization, and nuclear magnetic resonance spectroscopy as well as evaluation of their biological activities. These results identify rivulariapeptolides as a family of serine protease inhibitors with nanomolar potency, highlighting native metabolomics as a promising approach for drug discovery, chemical ecology, and chemical biology studies.
Keyphrases
- mass spectrometry
- liquid chromatography
- tandem mass spectrometry
- high performance liquid chromatography
- liquid chromatography tandem mass spectrometry
- gas chromatography
- simultaneous determination
- high resolution
- solid phase extraction
- ultra high performance liquid chromatography
- ms ms
- drug discovery
- high resolution mass spectrometry
- capillary electrophoresis
- high throughput
- binding protein
- mental health
- risk assessment
- genome wide
- human health
- dna methylation
- cancer therapy
- amino acid
- transcription factor
- single cell
- sensitive detection