Chemical synthesis of a cyclotide via intramolecular cyclization of peptide O-esters |
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Authors: | Ji-Shen Zheng Hao-Nan Chang Jing Shi Lei Liu |
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Affiliation: | 1. Department of Chemistry, University of Science and Technology of China, Hefei, 230026, China 2. State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, 100191, China 3. Department of Chemistry, Tsinghua University, Beijing, 100084, China
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Abstract: | Cyclotides constitute a fascinating family of circular proteins containing ca. 30 amino acid residues. They have a unique cyclic cysteine knot topology and exhibit remarkable thermal, chemical and enzymatic stabilities. These characteristics enable them to have a range of biological activities and promising pharmaceutical and agricultural applications. Here, we present a practical strategy for the chemical synthesis of cyclotides through the intramolecular ligation of fully unprotected peptide O-esters. This strategy involves the mild Fmoc solid-phase peptide synthesis of the peptide O-ester backbone, the head-to-tail cyclization of the cyclotide backbone by native chemical ligation, and the oxidative refolding to yield the natural knot protein. The simplicity and high efficiency of the strategy can be employed in the synthesis of artificial cyclotides for pharmaceutical applications. |
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Keywords: | cyclotides chemical synthesis peptide O-ester native chemical ligation macrolactamization |
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