posted on 2021-10-18, 14:06authored byMuhammad
N. Ahmed, Matti Wahlsten, Jouni Jokela, Matthias Nees, Ulf-Håkan Stenman, Danillo O. Alvarenga, Tomas Strandin, Kaarina Sivonen, Antti Poso, Perttu Permi, Mikko Metsä-Ketelä, Hannu Koistinen, David P. Fewer
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.