Recent results have highlighted the importance of argyrins, identifying them as non-competitive inhibitors of the human immunoproteasome (Allardyce and Bell, 2019). Among various compound classes with immunomodulatory activity, the best known examples are cyclosporine (Canafax and Ascher, 1983), FK506 (Wallemacq and Reding, 1993) and rapamycin (Dumont and Su, 1995), the latter approved for application in humans by the FDA in 1999 (Mann, 2001). Natural product-based immunosuppressive agents have been used for decades in human medical applications, e.g., to prevent organ rejections after transplantation. 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. Importantly, engineering of transcription and translation initiation resulted in a substantially improved production titre reaching 350–400 mg l −1. Furthermore, the optimization of cultivation conditions allowed exclusive production of one major derivative at a time, drastically improving the purification process. The system was also optimized to enable formation of methylated argyrin C and D derivatives with improved immunosuppressive activity compared with their unmethylated counterparts.

Eight novel argyrin derivatives were generated via biosynthetic engineering of the heterologous production system. An adenylation domain of the argyrin NRPS was characterized and shown to have a high preference for D-configured amino acids.

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.

Argyrins are formed by a non-ribosomal peptide synthetase (NRPS), originating from the myxobacterial producer strains Archangium gephyra Ar8082 and Cystobacter sp.

Argyrins 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.

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