A1 Journal article – refereed

Potent Inhibitor of Human Trypsins from the Aeruginosin Family of Natural Products




List of Authors: Ahmed Muhammad N., Wahlsten Matti, Jokela Jouni, Nees Matthias, Stenman Ulf-Håkan, Alvarenga Danillo O., Strandin Tomas, Sivonen Kaarina, Poso Antti, Permi Perttu, Metsä-Ketelä Mikko, Koistinen Hannu, Fewer David P.

Publisher: American Chemical Society

Publication year: 2021

Journal: ACS Chemical Biology

Journal name in source: ACS Chemical Biology

Volume number: 16

Issue number: 11

eISSN: 1554-8937

DOI: http://dx.doi.org/10.1021/acschembio.1c00611

URL: https://pubs.acs.org/doi/10.1021/acschembio.1c00611


Abstract

Serine proteases regulate many physiological processes and play a key role in a variety of cancers. Aeruginosins are a family of natural products produced by cyanobacteria that exhibit pronounced structural diversity and potent serine protease inhibition. Here, we sequenced the complete genome of Nodularia sphaerocarpa UHCC 0038 and identified the 43.7 kb suomilide biosynthetic gene cluster. Bioinformatic analysis demonstrated that suomilide belongs to the aeruginosin family of natural products. We identified 103 complete aeruginosin biosynthetic gene clusters from 12 cyanobacterial genera and showed that they encode an unexpected chemical diversity. Surprisingly, purified suomilide inhibited human trypsin-2 and -3, with IC50 values of 4.7 and 11.5 nM, respectively, while trypsin-1 was inhibited with an IC50 of 104 nM. Molecular dynamics simulations suggested that suomilide has a long residence time when bound to trypsins. This was confirmed experimentally for trypsin-1 and -3 (residence times of 1.5 and 57 min, respectively). Suomilide also inhibited the invasion of aggressive and metastatic PC-3M prostate cancer cells without affecting cell proliferation. The potent inhibition of trypsin-3, together with a long residence time and the ability to inhibit prostate cancer cell invasion, makes suomilide an attractive drug lead for targeting cancers that overexpress trypsin-3. These results substantially broaden the genetic and chemical diversity of the aeruginosin family and suggest that aeruginosins may be a source of selective inhibitors of human serine proteases.


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Last updated on 2021-03-12 at 10:59