Buntin, Kathrin, Mrak, Peter, Pivk-Lukancic, Petra, Wollbrett, Severine, Drčar, Tjaša, Krastel, Philipp, Thibaut, Christian, Salcius, Michael, Gao, Xiaolin, Wang, Shaowen, Weber, Eric and Regenass, Hugo (2023) Generation of bioactivity-tailored FK506/FK520 analogs by CRISPR editing in Streptomyces tsukubaensis. Chemistry a european journal, 30 (3). n/a-n/a. ISSN 0947-6539

Abstract

For a potential application of FK506 in the treatment of acute kidney failure only the FKBP12 binding capability of the compound is required while the immunosuppressive activity via calcineurin binding is considered as a likely risk to the patients. The methoxy-groups at C13 and C15 are thought to have significant influence on the immunosuppressive activity of the molecule. Consequently, FK506 analogs with different functionalities at C13 and C15 were generated by targeted CRISPR editing of the AT domains in module 7 and 8 of the biosynthetic assembly line in Streptomyces tsukubaensis. In addition, the corresponding FK520 (C21 ethyl derivative of FK506) analogs could be obtained by media adjustments. The compounds were tested for their bioactivity in regards to FKBP12 binding, BMP potentiation and calcineurin sparing. 15-desmethoxy FK506 was superior to the other tested analogs by retaining its high potency towards FKBP12 binding and BMP potentiation, while calcineurin inhibition was abolished

Item Type:	Article
Keywords:	BMP potentiation, CRISPR editing, calcineurin sparing, FK506, PKS type I engineering
Date Deposited:	30 Jan 2024 00:45
Last Modified:	30 Jan 2024 00:46
URI:	https://oak.novartis.com/id/eprint/50878