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Cyclotriveratrylene (CTV) as a New Chiral Triacid Scaffold Capable of Inducing Triple Helix Formation of Collagen Peptides Containing either a Native Sequence or Pro‐Hyp‐Gly Repeats
Author(s) -
Rump Erik T.,
Rijkers Dirk T. S.,
Hilbers Hans W.,
de Groot Philip G.,
Liskamp Rob M. J.
Publication year - 2002
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/1521-3765(20021018)8:20<4613::aid-chem4613>3.0.co;2-r
Subject(s) - triple helix , scaffold , sequence (biology) , chemistry , helix (gastropod) , collagen helix , stereochemistry , peptide , combinatorial chemistry , biochemistry , biology , medicine , biomedical engineering , snail , ecology
A new triacid scaffold is described based on the cone‐shaped cyclotriveratrylene (CTV) molecule that facilitates the triple helical folding of peptides containing either a unique blood platelet binding collagen sequence or collagen peptides composed of Pro‐Hyp‐Gly repeats. The latter were synthesized by segment condensation using Fmoc‐Pro‐Hyp‐Gly‐OH. Peptides were coupled to this CTV scaffold and also coupled to the Kemp's triacid (KTA) scaffold. After assembly of peptide H‐Gly‐[Pro‐Hyp‐Gly] 2 ‐Phe‐Hyp‐Gly‐Glu(OAll)‐Arg‐Gly‐Val‐Glu(OAll)‐Gly‐[Pro‐Hyp‐Gly] 2 ‐NH 2 ( 13 ) by an orthogonal synthesis strategy to both triacid scaffolds, followed by deprotection of the allyl groups, the molecular constructs spontaneously folded into a triple helical structure. In contrast, the non‐assembled peptides did not. The melting temperature ( T m ) of (+/−) CTV[CH 2 C(O)N(H)Gly‐[Pro‐Hyp‐Gly] 2 ‐Phe‐Hyp‐Gly‐Glu‐Arg‐Gly‐Val‐Glu‐Gly‐[Pro‐Hyp‐Gly] 2 ‐NH 2 ] 3 ( 14 ) is 19 °C, whereas KTA[Gly‐Gly‐[Pro‐Hyp‐Gly] 2 ‐Phe‐Hyp‐Gly‐Glu‐Arg‐Gly‐Val‐Glu‐Gly‐[Pro‐Hyp‐Gly] 2 ‐NH 2 ] 3 ( 15 ) has a T m of 20 °C. Thus, it was shown for the first time that scaffolds were also effective in stabilizing the triple helix of native collagen sequences. The different stabilizing properties of the two CTV enantiomers could be measured after coupling of racemic CTV triacid to the collagen peptide, and subsequent chromatographic separation of the diastereomers. After assembly of the two chiral CTV scaffolds to the model peptide H‐Gly‐Gly‐(Pro‐Hyp‐Gly) 5 ‐NH 2 ( 24 ), the (+)‐enantiomer of CTV 28 b was found to serve as a better triple helix‐inducing scaffold than the (−)‐enantiomer 28 a . In addition to an effect of the chirality of the CTV scaffold, a certain degree of flexibility between the CTV cone and the folded peptide was also shown to be of importance. Restricting the flexibility from two to one glycine residues resulted in a significant difference between the two collagen mimics 20 a and 20 b , whereas the difference was only slight when two glycine residues were present between the CTV scaffold and the peptide sequence in collagen mimics 30 a and 30 b .