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 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.

Marine Pharmacology in 2012–2013: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action

“…bisacetylenic alcohol ( 191 ) [184]; conicasterol E ( 192 ) [185]; 6”-debromohamacanthin A ( 193 ) [186]; dieckol ( 194 ) [187]; fructigenine A ( 195 ) [188]; geoditin A ( 196 ) [189]; gorgosterol ( 197 ) [190]; gracilioether B ( 198 ) [191]; gracilioether K ( 199 ) [192]; herdmanine K ( 200 ) [193]; hyrtioreticulin A ( 201 ) [194]; new Kunitz-type protease inhibitor InHVJ ( 202 ) [195]; jaspamide ( 203 ) [196]; latonduine A ( 204 ) [197]; leucettine L41 ( 205 ) [169]; manzamine A ( 206 ) [198]; nahuoic acid A ( 207 ) [199]; namalide ( 208 ) [200]; ningalins C and D ( 209 , 210 ) [201]; octaphlorethol A ( 114 ) [120]; petrosaspongiolide M ( 211 ) [202]; petrosiol A ( 212 ) [203]; phidianidine A ( 213 ) [204]; Poly-APS ( 214 ) [205]; Pseudoceratina sp. dibromotyrosine ( 215 ) [206]; pseudopterosin A ( 216 ) [207]; sargachromanol G ( 217 ) [208]; S. graminifolium polysaccharide ( 218 ) [209]; S. patens phloroglucinol ( 219 ) [210]; S. xiamenensis benzopyran ( 220 ) [211]; theonellasterol ( 221 ) [212]; toluquinol ( 222 ) [213]; and U. lactuca fatty acid ( 223 ) [214].…”

Bioactive Peptides Produced by Cyanobacteria of the Genus Nostoc: A Review

“…The strain also produces four namalides with anabaenopeptin-like scaffold but lacking two residues in the ring part (Ile/Val-CO[Lys-Ile/Val-Hph/Hty] [117]. This type of peptide was earlier reported from marine sponge Siliquariaspongia mirabilis collected off Nama Island (Federated States of Micronesia) [118] and from the Brazilian strain of cyanobacterium Sphaerospermopsis torques-reginae ITEP-024 [119]. Anabaenopeptins usually inhibit activity of carboxypeptidases [120,121], protein phosphatases [122], or/and serine proteases (trypsin, chymotrypsin) [27,37].…”

Genomic and Metabolomic Analyses of Natural Products in Nodularia spumigena Isolated from a Shrimp Culture Pond

“…CENA543 and S. torques-reginae ITEP-024 [75,76]. Namalides are cyclic tetrapeptides with an exogenous amino acid attached to the macrocycle by a urethane linkage and are structurally related to APT but lacking two amino acid residues [77]. These authors also reported the carboxypeptidase A inhibitory activity of namalide at submicromolar concentrations.…”