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  3. Native metabolomics identifies the rivulariapeptolide family of protease inhibitors

Native metabolomics identifies the rivulariapeptolide family of protease inhibitors

  • Nat Commun. 2022 Aug 8;13(1):4619. doi: 10.1038/s41467-022-32016-6.
Raphael Reher 1 2 3,  Allegra T Aron 4,  Pavla Fajtová 4,  Paolo Stincone 5,  Berenike Wagner 5 6,  Alicia I Pérez-Lorente 7,  Chenxi Liu 4,  Ido Y Ben Shalom 4,  Wout Bittremieux 4,  Mingxun Wang 4,  Kyowon Jeong 8,  Marie L Matos-Hernandez 9,  Kelsey L Alexander 1 10,  Eduardo J Caro-Diaz 9,  C Benjamin Naman 11,  J H William Scanlan 12,  Phil M M Hochban 12,  Wibke E Diederich 12,  Carlos Molina-Santiago 7,  Diego Romero 7,  Khaled A Selim 5 6,  Peter Sass 5 6,  Heike Brötz-Oesterhelt 5 6 13,  Chambers C Hughes 5 6 13,  Pieter C Dorrestein 4,  Anthony J O'Donoghue 4,  William H Gerwick 14 15,  Daniel Petras 16 17 18 19
Affiliations

Affiliations

  • 1 Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA.
  • 2 Institute of Pharmacy, Martin-Luther-University Halle-Wittenberg, Halle, Germany.
  • 3 Institute of Pharmaceutical Biology and Biotechnology, University of Marburg, Marburg, Germany.
  • 4 Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, CA, USA.
  • 5 Cluster of Excellence "Controlling Microbes to Fight Infections" (CMFI), University of Tuebingen, Tuebingen, Germany.
  • 6 Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tuebingen, Germany.
  • 7 Instituto de Hortofruticultura Subtropical y Mediterránea "La Mayora," Consejo Superior de Investigaciones Científicas, Departamento de Microbiología, Universidad de Málaga, Málaga, Spain.
  • 8 Applied Bioinformatics, Computer Science Department, University of Tuebingen, Tuebingen, Germany.
  • 9 Department of Pharmaceutical Sciences, School of Pharmacy, University of Puerto Rico - Medical Sciences Campus, San Juan, Puerto Rico.
  • 10 Department of Chemistry and Biochemistry, University of California San Diego, La Jolla, CA, USA.
  • 11 Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, Department of Marine Pharmacy, College of Food and Pharmaceutical Sciences, Ningbo University, Ningbo, China.
  • 12 Department of Pharmaceutical Chemistry and Center for Tumor Biology and Immunology (ZTI), University of Marburg, Marburg, Germany.
  • 13 German Center for Infection Research, Partner Site Tuebingen, Tuebingen, Germany.
  • 14 Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA. wgerwick@health.ucsd.edu.
  • 15 Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, CA, USA. wgerwick@health.ucsd.edu.
  • 16 Scripps Institution of Oceanography, University of California San Diego, La Jolla, CA, USA. daniel.petras@uni-tuebingen.de.
  • 17 Skaggs School of Pharmacy and Pharmaceutical Science, University of California San Diego, La Jolla, CA, USA. daniel.petras@uni-tuebingen.de.
  • 18 Cluster of Excellence "Controlling Microbes to Fight Infections" (CMFI), University of Tuebingen, Tuebingen, Germany. daniel.petras@uni-tuebingen.de.
  • 19 Interfaculty Institute of Microbiology and Infection Medicine, University of Tuebingen, Tuebingen, Germany. daniel.petras@uni-tuebingen.de.
PMID: 35941113 DOI: 10.1038/s41467-022-32016-6
Abstract

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.

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