Helix-stabilized cyclic peptides

Mi LZ, et al. Structural basis for bile acid binding and activation of the nuclear receptor FXR. Mol. Cell 2003 11 1093-1100. Leduc AM, et al. Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proc. Natl. Acad. Sci. U.S.A. 2003 100 11273-11278. 

Leduc, A.M., Trent, J.O., Wittliff, J.L., Bramlett, K.S., Briggs, S.L., Chirgadze, N.Y., Wang, Y., Burris, T.P. and Spatola, A.F. (2003) Helix-stabilized cyclic peptides as selective inhibitors of steroid receptor-coactivator interactions. Proceedings of the National Academy of Sciences of the United States of America, 100, 11273-11278. 

Robust peptide-derived approaches aim to identify a small drug-like molecule to mimic the peptide interactions. The primary peptide molecule is considered in these approaches as a tool compound to demonstrate that small molecules can compete with a given interaction. A variety of chemical, 3D structural and molecular modeling approaches are used to validate the essential 3D pharmacophore model which in turn is the basis for the design of the mimics. The chemical approaches include in addition to N- and C-terminal truncations a variety of positional scanning methods. Using alanine scans one can identify the key pharmacophore points D-amino-acid or proline scans allow stabilization of (i-turn structures cyclic scans bias the peptide or portions of the peptide in a particular conformation (a-helix, (i-turn and so on) other scans, like N-methyl-amino-acid scans and amide-bond-replacement (depsi-peptides) scans aim to improve the ADME properties." ... 

A detailed oxidation study on an artificially designed palindromic peptide with a predicted high tendency to form antiparallel a-helices confirmed that stabilization of the a-helix by increasing amounts of TFE allowed the control of the product distribution in favor of the antiparallel dimer to a certain degree, although increasing amounts of cyclic trimers were formedi106 In the absence of or at low levels of TFE, formation of the cyclic monomer was predominant. 

Seebach and co-workers have developed hetero-hexa-/j-peptides, e.g., 8 (Chart 1), which form helical structures in water as well as in organic solvents.32 They demonstrated that the conformational restrictions in the backbone imposed by the use of cyclic monomers were not a prerequisite for the formation of these helical structures. Gellman s group later showed, however, that the incorporation of cyclic /1-amino acids in the sequence does have a positive effect on the stabilization of the helix.33 Exploring the possibilities of these types of monomers, Seebach and co-workers demonstrated that also /3-sheets and turns can be realized,34 and that the 14-helix can also be attained through the use of y-amino acids.35... 

In the right-handed a-helix, the peptide chain forms a helix (like a cork screw) with the side groups on the outside, where each turn takes 3.6 residues (18 residues making 5 turns) the translation of the helix is 0.15 nm per residue (i.e., a pitch of 0.54 nm per turn), compared to 0.36 nm per residue for a stretched chain (Figure 7.2). The helical conformation is stabilized by H-bonds, between the O of peptide bond i and the NH of peptide bond i + 4. Moreover, enhanced van der Waals attraction is involved. The possibility for the latter to occur varies among amino acid residues, which means that not all of them readily partake in an a-helix. Ala, Glu, Phe, His, lie, Leu, Met, Gin, Val, and Trp have strong tendencies to form helices, whereas Pro, owing to its cyclic structure, is a helix breaker. ... 

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