Native metabolomics identifies the rivulariapeptolide family of protease inhibitors

Raphael Reher, Allegra T. Aron, Pavla Fajtová, Paolo Stincone, Berenike Wagner, Alicia I. Pérez-Lorente, Chenxi Liu, Ido Y. Ben Shalom, Wout Bittremieux, Mingxun Wang, Kyowon Jeong, Marie L. Matos-Hernandez, Kelsey L. Alexander, Eduardo J. Caro-Diaz, C. Benjamin Naman, J. H. William Scanlan, Phil M. M. Hochban, Wibke E. Diederich, Carlos Molina-Santiago, Diego Romero, Khaled A. Selim, Peter Sass, Heike Brötz-Oesterhelt, Chambers C. Hughes, Pieter C. Dorrestein, Anthony J. O’Donoghue, William H. Gerwick () and Daniel Petras ()
Additional contact information
Raphael Reher: University of California San Diego
Allegra T. Aron: University of California San Diego
Pavla Fajtová: University of California San Diego
Paolo Stincone: University of Tuebingen
Berenike Wagner: University of Tuebingen
Alicia I. Pérez-Lorente: Universidad de Málaga
Chenxi Liu: University of California San Diego
Ido Y. Ben Shalom: University of California San Diego
Wout Bittremieux: University of California San Diego
Mingxun Wang: University of California San Diego
Kyowon Jeong: University of Tuebingen
Marie L. Matos-Hernandez: University of Puerto Rico - Medical Sciences Campus
Kelsey L. Alexander: University of California San Diego
Eduardo J. Caro-Diaz: University of Puerto Rico - Medical Sciences Campus
C. Benjamin Naman: Ningbo University
J. H. William Scanlan: University of Marburg
Phil M. M. Hochban: University of Marburg
Wibke E. Diederich: University of Marburg
Carlos Molina-Santiago: Universidad de Málaga
Diego Romero: Universidad de Málaga
Khaled A. Selim: University of Tuebingen
Peter Sass: University of Tuebingen
Heike Brötz-Oesterhelt: University of Tuebingen
Chambers C. Hughes: University of Tuebingen
Pieter C. Dorrestein: University of California San Diego
Anthony J. O’Donoghue: University of California San Diego
William H. Gerwick: University of California San Diego
Daniel Petras: University of California San Diego

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32016-6

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