De Novo Discovery of Thiopeptide Pseudo-natural Products Acting as Potent and Selective TNIK Kinase Inhibitors.

ABSTRACT: Bioengineering of ribosomally synthesized and post-translationally modified peptides (RiPPs) is an emerging approach to explore the diversity of pseudo-natural product structures for drug discovery purposes. However, despite the initial advances in this area, bioactivity reprogramming of multienzyme RiPP biosynthetic pathways remains a major challenge. Here, we report a platform for de novo discovery of functional thiopeptides based on reengineered biosynthesis of lactazole A, a RiPP natural product assembled by five biosynthetic enzymes. The platform combines in vitro biosynthesis of lactazole-like thiopeptides and mRNA display to prepare and screen large (≥10¹²) combinatorial libraries of pseudo-natural products. We demonstrate the utility of the developed protocols in an affi

SUBMITTER: Vinogradov AA 

PROVIDER: S-EPMC9650704 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature