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Publication Abstract from PubMed

The peptide recifin A is the inaugural member of the structurally intriguing new fold referred to as a tyrosine-lock. Its central four stranded beta-sheet is stabilized by a unique arrangement in which three disulfide bonds and their interconnecting backbone form a ring that wraps around one of the strands, resulting in a Tyr side chain being buried in the molecular core. Here we aimed to establish a synthetic route to this complex class of natural products. Full length recifin A was successfully generated through native chemical ligation chemistry joining two 21 amino acid residue fragments. Surprisingly, reduced linear recifin A readily adopts the correct, topologically-complex fold via random oxidation of the cysteines, suggesting it is highly energetically favored. Utilizing our synthetic strategy, we generated five recifin A analogues to investigate the structural role of the central Tyr residue and provide the first insights into the structure activity relationship of recifin A towards its cancer target tyrosyl-DNA phosphodiesterase I.

Picking the tyrosine-lock: chemical synthesis of the tyrosyl-DNA phosphodiesterase I inhibitor recifin A and analogues.,Smallwood TB, Krumpe LRH, Payne CD, Klein VG, O'Keefe BR, Clark RJ, Schroeder CI, Rosengren KJ Chem Sci. 2024 Jun 14;15(33):13227-13233. doi: 10.1039/d4sc01976h. eCollection , 2024 Aug 22. PMID:39183914^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.