Key to the success of long peptide chemical synthesis is the chemoselective ligation reaction. The most successful ligation method is the native chemical ligation developed by Kent et al. We have developed a new peptide chemical synthesis method by ligation of peptide hydrazides that is complementary to native chemical ligation.

This method involves a chemoselective reaction between a C-terminal peptide hydrazide and a Cys-peptide to yield a native peptide bond. Notably, peptide hydrazides can be readily prepared through either Boc- or Fmoc-based solid phase peptide synthesis (SPPS). In addition, peptide hydrazide can be obtained through biological expression. Thus both total and semi-synthesis of proteins can be achieved with ligation of peptide hydrazides. More importantly, the ligation of peptide hydrazides enables sequential ligation in the N-to-C direction.

Using the strategy of SPPS and hydrazide-based native chemical ligation, we achieved to synthesis peptides as long as 304 aa, including histone H3 (135 aa), ribosomal protein S25 (142 aa), di-ubiquitin (152 aa), tri-ubiquitin (228 aa) and tetra-ubiquitin chain (304 aa). 

Scheme 1. Synthesis of full-length ribosomal protein S25 through the ligation of peptide hydrazides



1. Fang, G. M., Cui, H. K., Zheng, J. S. & Liu, L.  Chemoselective ligation of peptide phenyl esters with N-terminal cysteines. Chembiochem : a European journal of chemical  biology11, 1061-1065,  doi:10.1002/cbic.201000165 (2010).

2. Fang, G. M. et  al. Protein chemical synthesis by ligation of peptide hydrazides. Angewandte Chemie50, 7645-7649, doi:10.1002/anie.201100996 (2011). 

3. Fang, G. M., Wang, J. X. & Liu, L. Convergent  chemical synthesis of proteins by ligation of peptide hydrazides. Angewandte Chemie51, 10347-10350, doi:10.1002/anie.201203843 (2012). 

4. Huang, Y.  C. et al. Synthesis of autophagosomal  marker protein LC3-II under detergent-free conditions. Angewandte Chemie52,  4858-4862, doi:10.1002/anie.201209523 (2013).

5. Tang, S. et al. An efficient one-pot four-segment condensation method for  protein chemical synthesis. Angewandte  Chemie54, 5713-5717,  doi:10.1002/anie.201500051 (2015).

6. Wang, J. X. et al. Peptide o-aminoanilides as  crypto-thioesters for protein chemical synthesis. Angewandte Chemie54,  2194-2198, doi:10.1002/anie.201408078 (2015).

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