title: Discovery and synthesis of namalide reveals a new anabaenopeptin scaffold and peptidase inhibitor.
abstract: The discovery, structure elucidation, and solid-phase synthesis of namalide, a marine natural product, are described. Namalide is a cyclic tetrapeptide; its macrocycle is formed by only three amino acids, with an exocyclic ureido phenylalanine moiety at its C-terminus. The absolute configuration of namalide was established, and analogs were generated through Fmoc-based solid phase peptide synthesis. We found that only natural namalide and not its analogs containing l-Lys or l-allo-Ile inhibited carboxypeptidase A at submicromolar concentrations. In parallel, an inverse virtual screening approach aimed at identifying protein targets of namalide selected carboxypeptidase A as the third highest scoring hit. Namalide represents a new anabaenopeptin-type scaffold, and its protease inhibitory activity demonstrates that the 13-membered macrolactam can exhibit similar activity as the more common hexapeptides.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Cheruku
authors.forename: Alberto
authors.initials: A
authors.lastname: Plaza
authors.forename: Gianluigi
authors.initials: G
authors.lastname: Lauro
authors.forename: Jessica
authors.initials: J
authors.lastname: Keffer
authors.forename: John R
authors.initials: JR
authors.lastname: Lloyd
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bifulco
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bewley
mesh_terms: D000818:Animals; D043422:Carboxypeptidases A / Q000037:antagonists & inhibitors; D002918:Chymotrypsin / Q000037:antagonists & inhibitors; D008958:Models, Molecular; D008968:Molecular Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D011161:Porifera / Q000737:chemistry*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000302:isolation & purification; D060327:Solid-Phase Synthesis Techniques; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; C571183:namalide; D043422:Carboxypeptidases A; D002918:Chymotrypsin