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

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

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

Ahmed Muhammad N.
Stenman Ulf-Håkan
Permi Perttu
Wahlsten Matti
Fewer David P.
Jokela Jouni
Koistinen Hannu
Sivonen Kaarina
Metsä-Ketelä Mikko
Nees Matthias
Strandin Tomas
Alvarenga Danillo O.
Poso Antti
Katso/Avaa
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American Chemical Society
doi:10.1021/acschembio.1c00611
URI
https://pubs.acs.org/doi/10.1021/acschembio.1c00611
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Julkaisun pysyvä osoite on:
https://urn.fi/URN:NBN:fi-fe2021120859687
Tiivistelmä

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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