Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins

0556382 - MBÚ 2023 RIV GB eng J - Journal Article
Heinila, L. - Jokela, J. - Ahmed, M. - Wahlsten, M. - Saurav, Kumar - Hrouzek, Pavel - Permi, P. - Koistinen, H. - Fewer, D. - Sivonen, K.
Discovery of varlaxins, new aeruginosin-type inhibitors of human trypsins.
Organic & Biomolecular Chemistry. Roč. 20, č. 13 (2022), s. 2681-2692. ISSN 1477-0520. E-ISSN 1477-0539
Institutional support: RVO:61388971
Keywords : biosynthetic gene-cluster * nostoc sp * identification * evolution * 298-a * prss3/mesotrypsin * microcystis * expression * resistance * peptides
OECD category: Organic chemistry
Impact factor: 3.2, year: 2022
Method of publishing: Open access
https://pubs.rsc.org/en/content/articlelanding/2022/OB/D1OB02454J

Low-molecular weight natural products display vast structural diversity and have played a key role in the development of novel therapeutics. Here we report the discovery of novel members of the aeruginosin family of natural products, which we named varlaxins. The chemical structures of varlaxins 1046A and 1022A were determined using a combination of mass spectrometry, analysis of one- and two-dimensional NMR spectra, and HPLC analysis of Marfey's derivatives. These analyses revealed that varlaxins 1046A and 1022A are composed of the following moieties: 2-O-methylglyceric acid 3-O-sulfate, isoleucine, 2-carboxy-6-hydroxyoctahydroindole (Choi), and a terminal arginine derivative. Varlaxins 1046A and 1022A differ in the cyclization of this arginine moiety. Interestingly, an unusual alpha-d-glucopyranose moiety derivatized with two 4-hydroxyphenylacetic acid residues was bound to Choi, a structure not previously reported for other members of the aeruginosin family. We sequenced the complete genome of Nostoc sp. UHCC 0870 and identified the putative 36 kb varlaxin biosynthetic gene cluster. Bioinformatics analysis confirmed that varlaxins belong to the aeruginosin family of natural products. Varlaxins 1046A and 1022A strongly inhibited the three human trypsin isoenzymes with IC50 of 0.62-3.6 nM and 97-230 nM, respectively, including a prometastatic trypsin-3, which is a therapeutically relevant target in several types of cancer. These results substantially broaden the genetic and chemical diversity of the aeruginosin family and provide evidence that the aeruginosin family is a source of strong inhibitors of human serine proteases.
Permanent Link: http://hdl.handle.net/11104/0331318