Potent Inhibitor of Human Trypsins from the Aeruginosin Family of Natural Products
Muhammad N. Ahmed, Matti Wahlsten, Jouni Jokela, Matthias Nees, Ulf‐Håkan Stenman, Danillo Oliveira Alvarenga, Tomas Strandin, Kaarina Sivonen, Antti Poso, Perttu Permi, Mikko Metsä‐Ketelä, Hannu Koistinen, David P. Fewer
Abstract
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.