Diaminodiacid Bridges to Improve Folding and Tune the Bioactivity of Disulfide‐Rich Peptides |
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| Authors: | Ye Guo De‐Meng Sun Feng‐Liang Wang Yao He Prof Lei Liu Prof Chang‐Lin Tian |
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| Institution: | 1. Tsinghua‐Peking Center for Life Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084 (China);2. Department of Chemistry, University of Science and Technology of China, Hefei 230026 (China);3. Hefei National Laboratory for Physical Sciences at the Microscale and School of Life Sciences, University of Science and Technology of China and High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230027 (China) |
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| Abstract: | Disulfide‐rich peptides containing three or more disulfide bonds are promising therapeutic and diagnostic agents, but their preparation is often limited by the tedious and low‐yielding folding process. We found that a single cystine‐to‐diaminodiacid replacement could significantly increase the folding efficiency of disulfide‐rich peptides and thus improve their production yields. The practicality of this strategy was demonstrated by the synthesis and folding of derivatives of the μ‐conotoxin SIIIA, the preclinical hormone hepcidin, and the trypsin inhibitor EETI‐II. NMR and X‐ray crystallography studies confirmed that these derivatives of disulfide‐rich peptide retained the correct three‐dimensional conformations. Moreover, the cystine‐to‐diaminodiacid replacement enabled structural tuning, thereby leading to an EETI‐II derivative with higher bioactivity than the native peptide. |
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| Keywords: | disulfide‐rich peptide peptide therapeutics peptide synthesis protein engineering protein folding |
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