Discovery and Synthesis of Namalide Reveals a New Anabaenopeptin Scaffold and Peptidase Inhibitor

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• 作者：Pradeep Cheruku ; Alberto Plaza ; Gianluigi Lauro ; Jessica Keffer ; John R. Lloyd ; Giuseppe Bifulco ; Carole A. Bewley
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：January 26, 2012
• 年：2012
• 卷：55
• 期：2
• 页码：735-742
• 全文大小：365K
• 年卷期：v.55,no.2(January 26, 2012)
• ISSN：1520-4804

文摘

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.