Helix mimetics

The a-helix is the most abundant secondary structural element, determining the functional properties of proteins as diverse as a-keratin, hemoglobin and the transcription factor GCN4. The average length of an a-helix in proteins is approximately 17 A, corresponding to 11 amino acid residues or three a-helical turns. In short peptides, the conformational transition from random coil to a-helix is usually entropically disfavored. Nevertheless, several methods are known to induce and stabilize a-helical conformations in short peptides, including  

As mentioned above, these three subunits were designed to form a first a-helical turn in which the four amide groups are ideally oriented to participate in the H-bond network of an a-helix. Peptides that are linked to these templates adopt an a-helical conformation due to the conformational constraint induced by the high inherent a-helix propensity of the template and the H-bond network that is initiated by the proper orientation of the carbonyl groups. Thus, helix induction is achieved by the combination of steric and electronic properties of the three subunits. 

The P-tetralin amino acid induces the a-helical conformation by fixing the torsional angles along the peptide backbone at about -60° ( ) and -50° ( p).109 P-Tetralin amino acids may be regarded as cyclic-constrained phenylalanine analogues. As shown in Section II.A, this class of unnatural amino acids is known to stabilize distinct conformations in peptides since the two substituents at the a-cen-ter restrict the available conformational space. Cyclic a,a-dialkylated glycines and a-substituted alanines preferentially adopt a-helical conformations.205 

A careful analysis of conformational energy maps (Ramachandran plots) revealed that both enantiomers of P-tetralin amino acids were compatible with the right handed a-helical conformation.109 This was an important prerequisite for the development of N- and C-caps since the ( -configuration of the P-tetralin amino acid is needed for N-terminal helix induction, whereas the (R)-enantiomer was used in the C-cap series. The fact that both configurations were compatible with a-helical conformations made these amino acids our first choice as building blocks for 

The fact that both N- and C-terminal a-helix induction was achieved using the same concept raised the question of whether it would be possible to combine the N- and C-cap concepts, by generating a position-independent template that stabilizes (J-helical conformations not only from N-terminal or C-terminal ends but also from internal positions. 

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There are few examples of C-terminal helix mimetics and, while their utility has been considered uncertain,11361 successful helix induction has been described using tetra-hydronaphthalene compounds represented by 16.11351 Templated peptide 17, for example, demonstrates 81% helix by CD while control peptide 18 exhibits only 50% helix under the same conditions (Scheme 7). For the preparation of tetrahydronaphthalene templates and their attachment to peptides, see refs.1134,1351... 

But a-helix mimetics of the scission site are not convincingly active. 

Lu SY, Jiang YJ, Zou JW, Wu TX (2011) Molecular modeling and molecular dynamics simulation studies on pyrrolopyrimidine-based alpha-helix mimetic as dual inhibitors of MDM2 and MDMX. J Mol Graph Model 30467-178... 

Chen F, Yin H, Sebti BFS, Hamilton AD, Chen J. p53 alpha-Helix mimetics antagonize p53/MDM2 interaction and activate p53. Mol. Cancer Therap. 2005 4 1019-1025. 

Patgiri (123) has recently reviewed replacement of hydrogen bonds within a peptide conformer with covalent bonds to stabilize particular conformation of the peptide (50, 121-123). Application of this approach has targeted both reverse-turn and helix mimetics. Numerous bicyclic and tricyclicdipeptide derivatives have been generated and incorporated into biologically active peptides (119,120). 

Peptides containing amino acids in which the a-proton has been replaced by a methyl group or other alkyl group (a,a-dialkyl amino acids) serve as the simplest example of helix mimetics. The severe restrictions of (p,v / space by an a-methyl amino acid to limit backbone conformations only to values associated with both a- and 310-heli-ces was discovered independently by Marshall and Bosshard (90) and by Burgess and Leach (171). These early predictions from molecular modeling have been confirmed by multiple studies, both computationally (172-175) and experimentally (176-183) in the subsequent 35 years. Numerous examples of the introduction of a-methyl amino acids into biologically... 

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). 

Cummings, M. D., Schubert, C., Parks, D. J., Calvo, R. R., LaFrance, L. V., Lattanze, J., Milkiewicz, K. L., and Lu, T. (2006) Substituted 1,4-benzodiazepine-2,5-diones as alpha-helix mimetic antagonists of the HDM2-p53 protein-protein interaction. Chem. Biol. Drug Des. 67, 201-205. 

Ernst, J. T., Becerril, J., Park, H. S., Yin, H., and Hamilton, A. D. (2003) Design and application of an alpha-helix-mimetic scaffold based on an oligoamide-foldamer strategy Antagonism of the Bak BH3/Bcl-xL complex. Angew. Chem. Int. Ed. Engl. 42, 535-539. 

Biros, S. M., Moisan, L., Mann, E., Carella, A., Zhai, D., Reed, J. C., and Rebek, J. Jr. (2007) Heterocyclic alpha-helix mimetics for targeting protein-protein interactions. Bioorg. Med. Chem. Lett. 17, 4641-4645. 

The most recent contribution to the field of CBIs comes from Hamilton et al. and is based on their helix mimetic biaryl scaffolds [65], By providing their scaffold with either aliphatic of benzylic substituents, CBIs were developed that showed inhibitory properties in the low micromolar regime (9, Figure 2.3) [66], These are the most potent small-molecule CBIs for the ER to date, and offer ample opportunity for optimization and investigation of cross-reactivity and selectivity. 

Becerril, J. and Hamilton, A.D. (2007) Helix mimetics as inhibitors of the interactions of the estrogen receptor with coactivator peptides. Angewandte Chemie, 119, 4555 1557. 

Saraogi I, Hamilton AD (2008) alpha-Helix mimetics as inhibitors of protein-protein interactions. Biochem Soc Trans 36(Pt 6) 1414-1417... 

Keywords Helix mimetics Inhibitors Protein-protein interactions... 

Complexes that feature a-helices at interfaces were studied because a-helices constitute the largest class of protein secondary structure and mediate many protein interactions [30, 51]. Helices located within the protein core are vital for the overall stability of protein tertiary structure, whereas exposed a-helices on protein surfaces constitute central bioactive regions for the recognition of numerous proteins, DNAs, and RNAs. Importantly, helix mimetics have emerged as a highly effective class of PPI inhibitors [32, 36, 44, 52-55]. 

From the above described analysis, there were 159 complexes predicted to be targets for small molecules and another 252 interfaces that could potentially be inhibited by helix mimetics. The remaining complexes that did not meet the criteria... 

In this section, the composition and characteristics of helical domains identified to be critical for protein complex formation is discussed. This analysis allows prediction of the type of helix mimetic that is best suited for the type of helical interface. 

Fig. 7 Potential of various helix mimetics to reproduce functionality of one, two, or all three faces of protein a-helices (Reprinted with permission from Bullock et al. [67], Copyright (2011) American Chemical Society)...

Fig. 13 Stabilized helices and nonnatural helix mimetics several strategies that stabilize the a-helical conformation in peptides or mimic this domain with nonnatural scaffolds have been described. Recent advances include [1-peptide helices, terphenyl helix-mimetics, mini-proteins, peptoid helices, side-chain crosslinked a-helices, and the hydrogen bond surrogate (HBS) derived a-helices. Circles represent amino acid side-chain functionality (Reprinted from Henchey et al. [52], Copyright (2008) with permission from Elsevier)...

Fig. 15 Inhibition of RSV F glycoprotein six-helix bundle formation to prevent virus-cell fusion. A heptad repeat (HR) C terminal domain lactam-bridged a-helix mimetic binds to the HR N terminal domain, preventing conformation change (Reprinted with permission from Shepherd et al. [109], Copyright (2006) American Chemical Society)...

Fig. 23 Nonpeptidic helix mimetics such as (b) terphenyls and (c) pyridylpyridone derivatives array protein like functionality to mimic their arrangement on an a-helix (a) (Reprinted from Guarracino et al. [148], Copyright (2011) with permission from Wiley)...

Cummings CG, Hamilton AD (2010) Disrupting protein-protein interactions with non-peptidic, small molecule a-helix mimetics. Curr Opin Chem Biol 14 341-346... 

Marimganti S, Cheemala MN, Ahn JM (2009) Novel amphiphilic a-helix mimetics based on a bis-benzamide scaffold. Org Lett 11 4418 1421... 

Shaginian A, Whitby LR, Hong S et al (2009) Design, synthesis, and evaluation of an a-helix mimetic library targeting protein-protein interactions. J Am Chem Soc 131 5564—5572... 

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