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. 2010 Sep 17;49(39):7049-53.
doi: 10.1002/anie.201001900.

Traceless ligation of cysteine peptides using selective deselenization

Norman Metanis  1 , Ehud Keinan, Philip E Dawson
Affiliations

Traceless ligation of cysteine peptides using selective deselenization

Norman Metanis et al. Angew Chem Int Ed Engl. .
No abstract available

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Figures

Figure 1
Figure 1
HPLC chromatogram for the deselenization reaction mixture of peptide 5b, which was carried out with 9.4 equiv DTT for 1 h, and 2.2 equiv TCEP for 2 h to give major product, 6, with traces of the deselenized-desulfurized product, 7. Met(=O) corresponds to deselenized product with oxidized Met present in the starting material.
Scheme 1
Scheme 1
Native Chemical Ligation of N-terminal Sec-peptide 1 with C-terminal thioester-peptide 2 gives the ligated product, 3a. Following purification, 3a was deselenized to the alanyl peptide 4, using excess TCEP. R = 3-mercaptopropionyl-Leu.
Scheme 2
Scheme 2
Selective deselenization of peptide 5b. The deselenized peptide 6 was the major product with only traces of side product, 7.
Scheme 3
Scheme 3
Proposed deselenization mechanism of Sec-containing peptides with TCEP in aqueous solution.
Scheme 4
Scheme 4
Reaction of dimer peptide 1 with H2O2 produced the dehydroalanine analog, 8, which was rapidly hydrolyzed under the reaction conditions to the corresponding pyruvoyl peptide 9a (in equilibrium with its hydrate 9b). In contrast, reaction of peptide 1 with TCEP gave only the deselenized product, 10, with an N-terminal Ala.
Scheme 5
Scheme 5
Deselenization of peptide 5b in phosphate buffered D2O by TCEP forms two products; the deselenized mono-deuterated product, 6-d as the major product and the doubly-deuterated deselenized-desulfurized minor product, 7-d2.
Scheme 6
Scheme 6
The diselenide dimer of FKUSD, 11, was deselenized with 10 equiv TCEP in 200 mM phosphate buffer, pH 5.1 to give only FK(l)ASD product, 12, no traces of the of 13 were observed.
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