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dc.contributor.authorPogorevc, Domen
dc.contributor.authorMüller, Rolf
dc.identifier.citationMicrob Biotechnol. 2021 Nov 1. doi: 10.1111/1751-7915.13959. Epub ahead of print.en_US
dc.description.abstractArgyrins represent a family of cyclic octapeptides exhibiting promising immunomodulatory activity via inhibiting mitochondrial protein synthesis, which leads to reduced IL-17 production by the T-helper 17 cells. Argyrins are formed by a non-ribosomal peptide synthetase (NRPS), originating from the myxobacterial producer strains Archangium gephyra Ar8082 and Cystobacter sp. SBCb004. In this work, a previously established heterologous production platform was employed to provide evidence of direct D-configured amino acid incorporation by the argyrin assembly line. An adenylation domain of the argyrin NRPS was characterized and shown to have a high preference for D-configured amino acids. Eight novel argyrin derivatives were generated via biosynthetic engineering of the heterologous production system. The system was also optimized to enable formation of methylated argyrin C and D derivatives with improved immunosuppressive activity compared with their unmethylated counterparts. Furthermore, the optimization of cultivation conditions allowed exclusive production of one major derivative at a time, drastically improving the purification process. Importantly, engineering of transcription and translation initiation resulted in a substantially improved production titre reaching 350-400 mg l-1 . The optimized system presented herein thus provides a versatile platform for production of this promising class of immunosuppressants at a scale that should provide sufficient supply for upcoming pre-clinical development.en_US
dc.publisherJohn Wiley & Sons LTDen_US
dc.rightsAttribution 4.0 International*
dc.titleBiotechnological production optimization of argyrins - a potent immunomodulatory natural product class.en_US
dc.contributor.departmentHIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.en_US
dc.identifier.journalMicrobial biotechnologyen_US
dc.source.journaltitleMicrobial biotechnology
dc.source.countryUnited States

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Attribution 4.0 International
Except where otherwise noted, this item's license is described as Attribution 4.0 International