De novo design of constrained and sequence-independent peptide scaffolds with topologically-formidable disulfide connectivities

We developed a novel approach for designing a class of constrained and sequence-independent peptide scaffolds with three or four disulfide bonds. Even specific peptide folds that have been considered to be topologically formidable can be de novo created and synthesized in high yields.


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2012, 51, 10347-10350. 2-Chlorotrityl chloride resin (1.5 g) was swelled in DMF (10 mL) for 15 min. hydrazine (0.5 mL) and DIEA (2 mL) were dissolved in DMF (5 mL). The above solution was then added dropwise into the resin and stirred for 1.5 h at room temperature. The reaction was quenched by adding 1 mL of methanol and then stirred for 20 min. The resulting resin was washed with DMF, H 2 O, DMF, MeOH and Et 2 O in sequence. The resin was then dried and determined to have a loading of 0.857 mmol/g.  The arrow indicates the cleavage site of trypsin digestion.
Note that Fragments a, c, d, e and f was a contaminant from isomer 3b that was difficult to remove, 4-6 pairing in fragment b was a contaminant from isomer 3b.  The arrow indicates the cleavage site of trypsin digestion.
Fragments a and g indicate the formation of 1-6, 2-4, 3-5.    The arrow indicates the cleavage site of trypsin digestion.

GCPR GPenGW
Fragment b:   The arrow indicates the cleavage site of trypsin digestion.
b*: the cleavage site within the GGPenGWKGCGGK fragment was not cleaved.