A new scaffold, TREN-(suc-OH)(3) where TREN is tris(2-aminoethyl)amine and suc is the succinic acid spacers, was incorporated to assemble triple helices composed of Gly-Nleu-Pro sequences (Nleu denotes N-isobutylglycine). Extensive biophysical studies which include denaturation studies, CD and NMR spectroscopy, and molecular modeling demonstrated that TREN-[suc-(Gly-Nleu-Pro)(n)-NH(2)](3) (n = 5 and 6) form stable triple helical structures in solution. A comparative analysis of TREN-assembled and KTA-assembled collagen mimetics (KTA denotes Kemp triacid, 1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid) indicates that the flexibility of the TREN scaffold is superior to the KTA scaffold in inducing triple helicity. This effect most likely arises from the flexibility of the TREN scaffold which allows the three peptide chains to adjust their register for a tighter triple helical packing.

Collagen peptidomimetics have been synthesized as an alternative to natural collagen. The incorporation of unnatural residues such as peptoids in the collagen sequences can demonstrate potent and specific biological activity and enhance the biostability against enzymatic degradation. Furthermore, the use of achiral peptoids simplifies synthetic strategies by reducing racemization problems. The peptoid residue N‐isobutylglycine (Nleu) has been successfully incorporated into a series of collagen mimetics composed of Gly‐Pro‐Nleu, Gly‐Nleu‐Pro, and Gly‐Nleu‐Nleu. The discovery of template‐assembled collagen mimetics and metal binding ability has laid the foundation for new opportunities in the design of novel collagen mimetic complexes. This review summarizes the synthesis and integrated biophysical analyses of the structures of these collagen mimetics. Solid phase segment condensation techniques have been utilized for the synthesis of the single chain and template‐assembled analogues. The characterization of the collagen‐like structures has been established by temperature‐dependent optical rotation measurements, CD, NMR spectroscopy, and molecular modelling simulations. © 1998 John Wiley & Sons, Inc. Biopoly 47: 127–142, 1998

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Collagen mimetic peptides containing the peptoid residue Nleu (Goodman Bhumralkar, Jefferson, Kwak, Locardi. Biopolymers 1998;47:127-142) were tested for interactions with epithelial cells and fibroblasts. Molecules containing the sequence Gly-Pro-Nleu with a minimum of nine repeats showed cell binding activity. The activity of these molecules appeared to be conformationally sensitive, with the triple-helical form being preferred. When immobilized on a surface, the (Gly-Pro-Nleu)(10)-Gly-Pro-NH(2) sequence stimulated the attachment and growth of corneal epithelial cells and fibroblasts and the migration of epithelial tissue. The peptide sequence KDGEA inhibited cell attachment to the (Gly-Pro-Nleu)(10)-Gly-Pro-NH(2) sequence, suggesting that cell binding to this collagen mimetic involves the alpha2beta1 heterodimer integrin receptor. Interestingly, peptides containing the sequence (GlyNleu-Pro-)(10)-NH(2) did not have cell binding activity. The discovery that triple-helical peptides containing the Gly-Pro-Nleu sequences interact with cells opens up new opportunities in the design of collagen mimetic biomaterials.