Accessing Diverse Pyridine-Based Macrocyclic Peptides by a Two-Site Recognition Pathway.
- Resource Type
- Academic Journal
- Authors
- Nguyen DT; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Le TT; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Rice AJ; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Hudson GA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; van der Donk WA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Howard Hughes Medical Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Mitchell DA; Department of Chemistry, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, United States.
- Source
- Publisher: American Chemical Society Country of Publication: United States NLM ID: 7503056 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-5126 (Electronic) Linking ISSN: 00027863 NLM ISO Abbreviation: J Am Chem Soc Subsets: MEDLINE
- Subject
- Language
- English
Macrocyclic peptides are sought-after molecular scaffolds for drug discovery, and new methods to access diverse libraries are of increasing interest. Here, we report the enzymatic synthesis of pyridine-based macrocyclic peptides (pyritides) from linear precursor peptides. Pyritides are a recently described class of ribosomally synthesized and post-translationally modified peptides (RiPPs) and are related to the long-known thiopeptide natural products. RiPP precursors typically contain an N-terminal leader region that is physically engaged by the biosynthetic proteins that catalyze modification of the C-terminal core region of the precursor peptide. We demonstrate that pyritide-forming enzymes recognize both the leader region and a C-terminal tripeptide motif, with each contributing to site-selective substrate modification. Substitutions in the core region were well-tolerated and facilitated the generation of a wide range of pyritide analogues, with variations in macrocycle sequence and size. A combination of the pyritide biosynthetic pathway with azole-forming enzymes was utilized to generate a thiazole-containing pyritide (historically known as a thiopeptide) with no similarity in sequence and macrocycle size to the naturally encoded pyritides. The broad substrate scope of the pyritide biosynthetic enzymes serves as a future platform for macrocyclic peptide lead discovery and optimization.