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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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Sugar amino acids (SAAs) were designed as new building blocks carrying an amino group and a carboxyl group on a carbohydrate scaffold. By exploiting standard solid- and solution-phase coupling procedures, linear and cyclic homooligomers containing glucosyluronic acid methylamine (Gum) were synthesized. We achieved a high yield and a very short coupling time for the oligomerization and cyclization of sequences encompassing two, three, four, and six Gum units. The synthesis of cyclic oligomers containing only SAAs as repetitive units has not been reported before. The conformational preferences in aqueous solution of the cyclic derivatives and their applications as potential host molecules are described herein. Benzoic acid and p-nitrophenol were chosen as model guest molecules to study the formation of cyclodextrin-like inclusion complexes. The complexation behavior of the cyclic hexamer was proved from three different points of view: chemical shifts, longitudinal relaxations (T(1)), and diffusion coefficients. All of them showed different values for host and guest molecules measured independently and in the presence of each other.

Blockade of the bradykinin B(2) receptor provides therapeutic benefit in hereditary angioedema (HAE) and potentially in many other diseases. Herein, we describe the development of highly potent B(2) receptor antagonists with a molecular weight of approximately 500 g/mol. First, known quinoline-based B(2) receptor antagonists were stripped down to their shared core motif 53, which turned out to be the minimum pharmacophore. Targeted modifications of 53 resulted in the highly water-soluble lead compound 8a. Extensive exploration of its structure-activity relationship resulted in a series of highly potent B(2) receptor antagonists, featuring a hydrogen bond accepting functionality, which presumably interacts with the side chain of Asn-107 of the B(2) receptor. Optimization of the microsomal stability and cytochrome P450 inhibition eventually led to the discovery of the highly potent and orally available B(2) receptor antagonist 52e (JSM10292), which showed the best overall properties.

This report represents initial studies of collagen mimetics with achiral peptoid-based trimeric sequences. The incorporation of achiral units into collagen-like structures is of considerable interest for the structural simplification of collagen-like biomaterials. The achiral unit Gly-Nleu-Nleu (where Nleu represents N-isobutylglycine) was positioned between Gly-Pro-Hyp trimeric repeats in collagen-like structures in order to examine the effect of an achiral block on triple helicity. A series of single chain structures, Ac-(Gly-Pro-Hyp) n -(Gly-Nleu-Nleu) n -(Gly-Pro-Hyp) n -NH2 (where n = 1−3), and a template-assembled structure, KTA-[Gly-(Gly-Pro-Hyp)2-(Gly-Nleu-Nleu)2-(Gly-Pro-Hyp)2-NH2]3 (where KTA represents cis,cis-1,3,5-trimethylcyclohexane-1,3,5-tricarboxylic acid), were investigated. Biophysical studies were carried out in both H2O and ethylene glycol (EG)/H2O (2:1, v/v) solvents, using circular dichroism and optical rotation measurements. Highly cooperative melting curves from optical rotation determinations were obtained for Ac-(Gly-Pro-Hyp) n -(Gly-Nleu-Nleu) n -(Gly-Pro-Hyp) n -NH2 (n = 2, 3) and KTA-[Gly-(Gly-Pro-Hyp)2-(Gly-Nleu-Nleu)2-(Gly-Pro-Hyp)2-NH2 ]3, revealing that the achiral trimer can participate in triple helical structures. These results were also supported by circular dichroism spectroscopy. For the molecules Ac-(Gly-Pro-Hyp)3-(Gly-Nleu-Nleu)3-(Gly-Pro-Hyp)3-NH2 and KTA-[Gly-(Gly-Pro-Hyp)2-(Gly-Nleu-Nleu)2-(Gly-Pro-Hyp)2-NH2]3, the presence of collagen-like structures was also supported by 1H NMR spectroscopy in H2O. For each structure, a distinct set of resonances, obtained at low temperature, disappeared once a thermal denaturation temperature was reached. Furthermore, the analysis of NOE cross-peaks established the close packing of Pro, Hyp, and Nleu. The spatial proximity of Pro and Nleu residues and of Hyp and Nleu residues belonging to different chains was confirmed by molecular modeling of triple helical Ac-(Gly-Pro-Hyp)3-(Gly-Nleu-Nleu)3-(Gly-Pro-Hyp)3-NH2.