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Organic & Biomolecular Chemistry
Page 4 of 4
COMMUNICATION
Journal Name
providing the correctly folded somatostain with an isolated
yield of 68% (Fig. 4).
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Furthermore, by using the same strategy, we also obtained
the host-defense skin peptide Riparin 1.1b containing one
disulfide bond (Fig. S12).13 As expected, chemical synthesis of
Riparin 1.1b was smooth. Riparin 1.1b hydrazide was readily
prepared from the hydrazine-trityl(2-Cl) resin in an isolated
yield of 73%. Riparin 1.1b hydrazide was cleanly converted to
Riparin 1.1b acid in a high isolated yield (71%) through the
NaNO2/MPAA/mercaptoethanol treatment. Under the
GSH/GSSG condition, Riparin 1.1b peptide acid was efficiently
folded into the desired Riparin 1.1b with an isolated yield of 65%.
Finally, we tested the utility of the new method for synthesis
of -conotoxin Vc1.1 containing two pairs of disulfide bonds.
This 16 amino acid peptide can alleviate neuropathinc pain in
several rat models.14 The Vc1.1 hydrazide (8) was readily
prepared by Fmoc-based solid phase synthesis using hydrazine-
trityl(2-Cl) resin with an isolated yield of 68% (Fig. 5). After
sequential treatment with NaNO2, MPAA and mercaptoethanol,
this polypeptide hydrazide was almost quantitatively converted
to the unfolded Vc1.1 acid (9). Under the redox conditions of
GSH/GSSG, a disulfide bond was formed between Cys3 and
Cys16, affording 10 in a high analytical yield (82%). Upon
addition of I2, the side chain Acm-protecting group of Cys2 and
Cys8 was removed, followed by the formation of the second
disulfide bond (Fig. 5). The desired Vc 1.1 was isolated in 70%
yield.
To summarize, we have developed a new robust strategy for
the synthesis of C-terminal Cys-containing peptide acids. The
peptide hydrazide-based strategy has the following advantages:
1) C-terminal Cys hydrazide peptides can be readily prepared by
using low-cost hydrazine-trityl(2-Cl) resin; 2) Fmoc SPPS of C-
terminal Cys hydrazide peptides does not show any side
reactions of epimerization and -elimination at the C-terminal
Cys; 3) through the NaNO2/MPAA/mercaptoethanol treatment,
C-terminal hydrazide peptides can be cleanly converted to the
desired C-terminal Cys peptide acids. The utility of this method
has been demonstrated in the synthesis of C-AhPDF1.1b,
somatostatin, Riparian 1.1b, and -conotoxin Vc1.1 acid. Taken
together, the new method offers an efficient and practical
strategy for the preparation of C-terminal Cys peptide acids. Use
of the new method for the development of peptide
therapeutics and diagnositics is undergoing in our laboratory
and will be reported in due course.
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This work was supported by the National Key R&D Program
of China (2017YFA0505200), National Natural Science
Foundation of China (No. 21572214, 21807001, 91753205).
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
(a) M. Góngora-Benítez, J. Tulla-Puche and F. Albericio, Chem.
Rev., 2014, 114, 901-926; (b) X. Xu and R. Lai, Chem. Rev., 2015,
4 | J. Name., 2012, 00, 1-3
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