Helical Mimetics

D. C. Rees, H. M. G. Willems, The design of dipeptide helical mimetics. 

Yin H, et al. Terphenyl-based helical mimetics that disrupt the 146. p53/HDM2 interaction. Angew Chem. Int. Ed. Engl. 2005 44 2704-2707. 

Fig. 10a implies that shared (bifurcated) hydrogen bonds dominate the statistical picture of helical conformation in proteins and must be considered in helical mimetic design. 

Jacoby (187) and the Hamilton group (188-191) suggested that bis- or tris-aromatic residues could serve as scaffolds for helical mimetics. Che et al. have examined a variety of aromatic-based scaffolds as potential helix mimetics (192). Rebek and coworkers have suggested a central pyridazine ring (193) as well as a heterocyclic piperazine-based scaffold (194). Ahn and Han developed a facile synthesis of benzamides as potential helix mimetics (195). 

Oligoamide-, terephthalamide-, oligourea- and biphenyldicarboxamide-based a-helical mimetics Bcl-X[/Bak interaction inhibition Mimetics could successfully displace the BH3 domain of the Bak peptide from the Bcl-X[/Bak BH3 complex, with K, values in the low micromolar range [98, 99]... 

Shepherd NE, Hoang HN, Desai VS et al (2006) Modular a-helical mimetics with antiviral activity against respiratory syncitial virus. J Am Chem Soc 128 13284—13289... 

Terphenyl-based Helical Mimetics that Disrupt the Bd-xL/Bak Interaction... 

Fig. 4.3-6 (a) Surface displacement of residues on an a-helix surface, (b) Terphenyl-based a-helical mimetics. 

G. Ratcliffe, Targeted molecular diversity, design and development of non-peptide antagonists for cholecystokinin and tachykinin receptors, Immunopharmacology 1996, 33, 68-72 D.C. Horwell, W. Howson, G.S. Ratcliffe, H.M.G. Willems, The design of dipeptide helical mimetics the synthesis, tachykinin receptor affinity and conformational analysis of... 

As such, the magainins provide a useful initial target for peptoid-based peptido-mimetic efforts. Since the helical structure and sequence patterning of these peptides seem primarily responsible for their antibacterial activity and specificity, it is conceivable that an appropriately designed, non-peptide helix should be capable of these same activities. As previously described (Section 1.6.2), peptoids have been shown to form remarkably stable hehces, with physical characterishcs similar to those of peptide polyprohne type-I hehces (e.g. cis-amide bonds, three residues per helical turn, and 6A pitch). A faciaUy amphipathic peptoid helix design, based on the magainin structural motif, would therefore incorporate cationic residues, hydrophobic aromatic residues, and hydrophobic aliphathic residues with threefold sequence periodicity. 

In summary, these recently obtained results demonstrate that certain amphi-pathic peptoid sequences designed to mimic both the helical structure and approximate length of magainin helices are also capable of selective and biomimetic antibacterial activity. These antibacterial peptoids are helical in both aqueous buffer and in the presence of lipid vesicles. Ineffective (non-antibacterial) peptoids exhibit weak, random coil-like CD, with no spectral intensification in the presence of lipid vesicles. Selective peptoids exhibit stronger CD signals in bacterial-mimetic vesicles than in mammalian-mimetic vesicles. Non-selective peptoids exhibit intensely helical CD in both types of vesicles. 

M., and Goodman, M. Triple helical stabilities of guest-host collagen mimetic structures. Bioorg. Med. Chem. 1999, 7, 153-160. 

While the a-helix of L-a-peptides and the (M)-3i4 helix of the corresponding peptides have opposite polarity and helicity (see Section 2.2.3.1), the inserhon of two CH2 groups in the backbone of L-a-amino acids leave these two hehx parameters unchanged, both the a-helix and the 2.614-hehx of the resulting y" -peptides being right-handed and polarized from N to C terminus. In view of these similarities, the y-peptide hehcal fold might prove useful as a template to elaborate functional mimetics of bioachve a-polypeptides. 

Although biologically active helical y-peptides have not been reported so far, the striking structural similarities (polarity and helicity) between the a-helix of L-a-peptides and the (P)-2.6i4-hehx of y-peptides suggest that the 2.614-helical backbone might prove useful as a template for elaborating functional mimetics of a-helical surfaces and intervening in protein-protein interactions. 

Henin et al. [54] used ABF to model the association of Glycophorin A inside a membrane mimetic. GpA was modeled using two frara-membrane helical segments. The key interactions between the two segments are shown in Fig. 4.12. 

Structural and energetic properties of studied molecules strongly depend on the solvent membrane-mimetic media significantly promote formation of a-helices capable of traversing the bilayer, whereas a polar environment destabilizes a-helical conformation via reduction of solvent-exposed surface area and packing. 

This volume brings together most of these critical issues by highlighting recent advances in a number of core areas of peptidomimetic synthesis. Section 9 focuses on side-chain-modified peptides, Section 10 describes the preparation and use of a variety of peptide main-chain modifications. Combined side-chain- and main-chain-modified peptides are covered in Section 11. Finally, Section 12 provides chemistry leading to peptides incorporating secondary structure ((1- and y-turns, helices, p-sheets) mimetics and inducers. 

Protein helices generally adopt variations of the usual helix geometries depending on the environment. 1 The methods described in Sections 12.3.1 and 12.3.2 will refer only to the synthesis of peptides incorporating inducers and mimetics for the a- and 310-helices. 

The remainder of Section 14 deals with triple helices and collagen mimetic structures (Sections 14.2.3.1 and 14.2.4). A description of routes is included which covers the synthesis of triple-helical structures using template (scaffolds) from a Lys-Lys dimer (Section 14.2.4.1), Glu-Glu dimer (Section 14.2.4.2), and appropriate Cys-Cys branches (Section 14.2.4.3). The syntheses were carried out using solid-phase techniques. A scaffold (template) using the Kemp triacid is also presented (Section 14.2.4.4). Lastly, a chemoselective ligation is presented which joins appropriately defined reaction sites (Section 14.2.4.5).[23]... 

Kwak J, Capua AD, Locardi E, Goodman M. TREN (Tris(2-aminoethyl.amine) an effective scaffold for the assembly of triple helical collagen mimetic structures. J. Am. Chem. Soc. 2002 124 14085-14091. 

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