Disulfide-Rich Peptides

(1)Efficient synthesis of native disulfide-rich peptides


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  devised an efficient one-pot synthesis of peptides containing up to 4 disulfide bonds (snake toxin Mambalgin-1) using an  azide switch strategy combined with hydrazide-based native chemical ligation.  This method provides access to multi-milligram quantities of disulfide-rich peptides.

Figure 1. Synthesis of Mambalgin-1 using  the azide switch strategy combined with hydrazide-based native chemical  ligation.


(2) Diaminodiacid bridges to improve folding of disulfide-rich peptides


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 m-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.


Scheme  1.Synthetic  route for preparation of SIIIA-1 with variable pre-prepared diaminodiacids. Z=pyroglutamate

Reference:

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1. Cui, H. K. et al. Diaminodiacid-based solid-phase synthesis of peptide  disulfide bond mimics. Angewandte Chemie52, 9558-9562,  doi:10.1002/anie.201302197 (2013).

2. Pan, M. et al. One-pot hydrazide-based native chemical ligation for  efficient chemical synthesis and structure determination of toxin Mambalgin-1. Chem Commun (Camb),  doi:10.1039/c4cc00779d (2014).

3. Guo, Y. et al. Diaminodiacid Bridges to Improve Folding and Tune the  Bioactivity of Disulfide-Rich Peptides. Angewandte  Chemie54, 14276-14281,  doi:10.1002/anie.201500699 (2015).

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