Potent Inhibitor of Human Trypsins from the Aeruginosin Family of Natural Products,ACS Chemical Biology

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Potent Inhibitor of Human Trypsins from the Aeruginosin Family of Natural Products
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2021-10-18 , DOI: 10.1021/acschembio.1c00611
Muhammad N Ahmed _{1,

2} , Matti Wahlsten ₁ , Jouni Jokela ₁ , Matthias Nees _{3,

4} , Ulf-Håkan Stenman ₂ , Danillo O Alvarenga _{1,

5} , Tomas Strandin ₆ , Kaarina Sivonen ₁ , Antti Poso _{7,

8} , Perttu Permi _{9,

10} , Mikko Metsä-Ketelä ₁₁ , Hannu Koistinen ₂ , David P Fewer ₁

Affiliation

Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Viikinkaari 9, Biocenter 1, P.O. Box 56, Helsinki FIN-00014, Finland.
Department of Clinical Chemistry and Haematology, Faculty of Medicine, University of Helsinki and Helsinki University Hospital, Haartmaninkatu 8, P.O. Box 63, Helsinki FIN-00014, Finland.
Department of Biochemistry and Molecular Biology, Medical University in Lublin, ul. Chodzki 1, Lublin 20-093, Poland.
Institute of Biomedicine and Western Cancer Centre FICAN West, University of Turku, Turku 20101, Finland.
Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen DK-2100, Denmark.
Department of Virology, Faculty of Medicine, University of Helsinki, Haartmaninkatu 3, P.O. Box 21, Helsinki FIN-00014, Finland.
School of Pharmacy, University of Eastern Finland, P.O. Box 1627, Kuopio FIN-70211, Finland.
Dept. of Internal Medicine VIII, University Hospital Tübingen, Otfried-Müller-Strasse 14, Tübingen DE-72076, Germany.
Department of Biological and Environmental Science, University of Jyväskylä, P.O. Box 35, Jyväskylä FI-40014, Finland.
Department of Chemistry, Nanoscience Center, University of Jyväskylä, P.O. Box 35, Jyväskylä FI-40014, Finland.
Department of Biochemistry, University of Turku, Turku FIN-20014, Finland.

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.

中文翻译：

来自天然产物铜绿素家族的人胰蛋白酶的强效抑制剂

丝氨酸蛋白酶调节许多生理过程并在多种癌症中发挥关键作用。铜绿素是由蓝藻产生的天然产物家族，具有明显的结构多样性和有效的丝氨酸蛋白酶抑制作用。在这里，我们对球形结节菌UHCC 0038的完整基因组进行了测序，并鉴定了 43.7 kb 的 suomilide 生物合成基因簇。生物信息学分析表明，索米利特属于天然产物铜绿素家族。我们从 12 个蓝藻属中鉴定了 103 个完整的绿脓杆菌素生物合成基因簇，并表明它们编码了意想不到的化学多样性。令人惊讶的是，纯化的 suomilide 抑制人胰蛋白酶 2 和 -3，IC ₅₀值分别为 4.7 和 11.5 nM，而 trypsin-1 被 IC _50抑制104海里。分子动力学模拟表明，当与胰蛋白酶结合时，suomilide 具有较长的停留时间。胰蛋白酶 1 和 -3 的实验证实了这一点（驻留时间分别为 1.5 和 57 分钟）。Suomilide 还抑制侵袭性和转移性 PC-3M 前列腺癌细胞的侵袭，而不影响细胞增殖。对胰蛋白酶 3 的有效抑制，加上较长的停留时间和抑制前列腺癌细胞侵袭的能力，使 suomilide 成为一种有吸引力的药物先导药物，用于靶向过表达胰蛋白酶 3 的癌症。这些结果大大拓宽了铜绿素家族的遗传和化学多样性，并表明铜绿素可能是人类丝氨酸蛋白酶选择性抑制剂的来源。

更新日期：2021-11-19

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