Department of Microbiology, University of Potsdam, Karl-Liebknecht-Str. 24/25, 14476, Potsdam-Golm, Germany.
Department of Biotechnology and Biomedicine, Technical University of Denmark, Søltofts Plads, Building 221, DK-2800 Kgs., Lyngby, Denmark.
Chembiochem. 2022 Oct 19;23(20):e202200345. doi: 10.1002/cbic.202200345. Epub 2022 Sep 13.
Microviridins are a prominent family of ribosomally synthesized and posttranslationally modified peptides (RiPPs) featuring characteristic lactone and lactam rings. Their unusual cage-like architecture renders them highly potent serine protease inhibitors of which individual variants specifically inhibit different types of proteases of pharmacological interest. While posttranslational modifications are key for the stability and bioactivity of RiPPs, additional attractive properties can be introduced by functional tags. To date - although highly desirable - no method has been reported to incorporate functional tags in microviridin scaffolds or the overarching class of graspetides. In this study, a chemoenzymatic in vitro platform is used to introduce functional tags in various microviridin variants yielding biotinylated, dansylated or propargylated congeners. This straightforward approach paves the way for customized protease inhibitors with built-in functionalities that can help to unravel the still elusive ecological roles and targets of this remarkable class of compounds and to foster applications based on protease inhibition.
微病毒素是一类重要的核糖体合成后修饰肽(RiPPs),具有特征性的内酯和内酰胺环。它们独特的笼状结构使它们成为高度有效的丝氨酸蛋白酶抑制剂,其中个别变体特异性抑制具有药理意义的不同类型的蛋白酶。虽然翻译后修饰是 RiPPs 稳定性和生物活性的关键,但通过功能标签可以引入其他有吸引力的特性。迄今为止 - 尽管非常理想 - 尚未有报道报道在微病毒素支架或graspetide 类中引入功能标签的方法。在这项研究中,使用化学酶促体外平台在各种微病毒素变体中引入功能标签,得到生物素化、丹磺酰化或炔丙基化的同系物。这种简单直接的方法为具有内置功能的定制蛋白酶抑制剂铺平了道路,这些抑制剂可以帮助揭示这一显著化合物类别的仍然难以捉摸的生态作用和靶标,并促进基于蛋白酶抑制的应用。