ArticleJournal of the American Chemical Society2022
Accessing Diverse Pyridine-Based Macrocyclic Peptides by a Two-Site Recognition Pathway.
Article in Journal of the American Chemical Society, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 29 citations in OpenAlex.
- Beyond Simple Mimicry: Next-Generation Geometric Architectures and Future Paradigms in Small-Molecule and Macrocyclic Peptidomimetics.Angewandte Chemie (International ed. in English) · 2026Review
- Cyanamide-Induced Desulfhydration Enables Access to α,β-Dehydropeptides.Organic letters · 2026Article
- Repositioning the Leader Peptide in Graspetide Biosynthesis.Journal of the American Chemical Society · 2026Article
- Modular Synthesis of Pyritide-Inspired Macrocycles Featuring Bipyridine Motifs.Angewandte Chemie (International ed. in English) · 2025Article
- Aminoacyl-tRNA Specificity of a Ligase Catalyzing Non-ribosomal Peptide Extension.Journal of the American Chemical Society · 2025Article
- Peptidic Tryptophan Halogenation by a Promiscuous Flavin-Dependent Enzyme.Angewandte Chemie (International ed. in English) · 2025Article
- Assessing Substrate Scope of the Cyclodehydratase LynD by mRNA Display-Enabled Machine Learning Models.Biochemistry · 2025Article
- Synthetic Biology in Natural Product Biosynthesis.Chemical reviews · 2025Review
- Substrate recognition by a peptide-aminoacyl-tRNA ligase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Cell-free biosynthesis and engineering of ribosomally synthesized lanthipeptides.Nature communications · 2024Article
- Genome Mining for New Enzyme Chemistry.ACS catalysis · 2024Review
- A Compact Reprogrammed Genetic Code for De Novo Discovery of Proteolytically Stable Thiopeptides.Journal of the American Chemical Society · 2024Article
- Proteases Involved in Leader Peptide Removal during RiPP Biosynthesis.ACS bio & med chem Au · 2024Review
- Development and Challenges of Cyclic Peptides for Immunomodulation.Current protein & peptide science · 2024Review
- Deep Learning-Driven Library Design for theACS central science · 2023Article
- Advances on the biosynthesis of pyridine rings.Engineering microbiology · 2023Review
- Bioinspired Total Synthesis of Pyritide A2 through Pyridine Ring Synthesis.Angewandte Chemie (International ed. in English) · 2022Article
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.