|
|||||
|
|
Synthesis of Disulfide Surrogate Peptides Incorporating Large-Span Surrogate Bridges Through a Native-Chemical-Ligation-Assisted Diaminodiacid Strategy |
|
| Authors: | Qian Qu Shuai Gao Fangming Wu Meng-Ge Zhang Ying Li Long-Hua Zhang Dr Donald Bierer Prof Chang-Lin Tian Prof Ji-Shen Zheng Prof Dr Lei Liu |
| Institution: | 1. Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus, Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084 China
These authors contributed equally to this work.;2. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031 China These authors contributed equally to this work.;3. School of Life Sciences, Hefei National Laboratory for Physical Sciences at the Microscale, University of Science and Technology of China, Hefei, 230027 China;4. Bayer AG, Department of Medicinal Chemistry, Aprather Weg 18A, 42096 Wuppertal, Germany;5. High Magnetic Field Laboratory, Chinese Academy of Sciences, Hefei, 230031 China;6. Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus, Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing, 100084 China |
| Abstract: | The use of synthetic bridges as surrogates for disulfide bonds has emerged as a practical strategy to obviate the poor stability of some disulfide-containing peptides. However, peptides incorporating large-span synthetic bridges are still beyond the reach of existing methods. Herein, we report a native chemical ligation (NCL)-assisted diaminodiacid (DADA) strategy that enables the robust generation of disulfide surrogate peptides incorporating surrogate bridges up to 50 amino acids in length. This strategy provides access to some highly desirable but otherwise impossible-to-obtain disulfide surrogates of bioactive peptide. The bioactivities and structures of the synthetic disulfide surrogates were verified by voltage clamp assays, NMR, and X-ray crystallography; and stability studies established that the disulfide replacements effectively overcame the problems of disulfide reduction and scrambling that often plague these pharmacologically important peptides. |
| Keywords: | Chemische Proteinsynthese Cyclische Peptide Disulfide Native chemische Ligation Peptide |