Accessing Diverse Pyridine-Based Macrocyclic Peptides by a Two-Site Recognition Pathway
| Autor: | Dinh T. Nguyen, Tung T. Le, Andrew J. Rice, Graham A. Hudson, Wilfred A. van der Donk, Douglas A. Mitchell |
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| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Journal of the American Chemical Society. 144:11263-11269 |
| ISSN: | 1520-5126 0002-7863 |
| DOI: | 10.1021/jacs.2c02824 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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