title: Synthetic fermentation of bioactive non-ribosomal peptides without organisms, enzymes or reagents.
abstract: Microbial fermentation can rapidly provide potent compounds that can be easily screened for biological activity, and the active components can be isolated. Its success in drug discovery has inspired extensive efforts to modulate and control the products. In this Article, we document a 'synthetic fermentation' of bioactive, unnatural peptides 'grown' from small building blocks in water using amide-forming ligations. No organisms, enzymes or reagents are needed. The sequences, structures and compositions of the products can be modulated by adjusting the building blocks and conditions. No specialized knowledge of organic chemistry or handling of toxic material is required to produce complex organic molecules. The 'fermentations' can be conducted in arrays and screened for biological activity without isolation or workup. As a proof-of-concept, about 6,000 unnatural peptides were produced from just 23 building blocks, from which a hepatitis C virus NS3/4A protease inhibitor with a half-maximum inhibitory concentration of 1.0 μM was identified and characterized.
authors.affiliation: Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Huang
authors.affiliation: 1] Laboratorium für Organische Chemie, Department of Chemistry and Applied Biosciences, ETH-Zürich, 8093 Zürich, Switzerland [2] Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Chikusa, Nagoya 464-8602, Japan.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Bode
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism*; D001419:Bacteria / Q000378:metabolism; D061249:Batch Cell Culture Techniques; D007555:Isoxazoles / Q000737:chemistry; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism*; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D007555:Isoxazoles; D010455:Peptides; D011480:Protease Inhibitors; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases