No abstract

Proteins and RNA are unique among known polymers in their ability to adopt compact and well-defined folding patterns. These two biopolymers can perform complex chemical operations such as catalysis and highly selective recognition, and these functions are linked to folding in that the creation of an active site requires proper juxtaposition of reactive groups. So the development of new types of polymeric backbones with well-defined and predictable folding propensities ('foldamers') might lead to molecules with useful functions. The first step in foldamer development is to identify synthetic oligomers with specific secondary structural preferences. Whereas alpha-amino acids can adopt the well-known alpha-helical motif of proteins, it was shown recently that beta-peptides constructed from carefully chosen beta-amino acids can adopt a different, stable helical conformation defined by interwoven 14-membered-ring hydrogen bonds (a 14-helix; Fig. 1a). Here we report that beta-amino acids can also be used to design beta-peptides with a very different secondary structure, a 12-helix (Fig. 1a). This demonstrates that by altering the nature of beta-peptide residues, one can exert rational control over the secondary structure.

Synthetic protocols and circular dichroism (CD) spectra are reported for a series of oligomers of (R,R)-trans-2-aminocyclopentanecarboxylic acid (trans-ACPC). The two longest oligomers, a hexamer and an octamer, have also been examined crystallographically. Both crystal structures show that the β-peptide backbone adopts a regular helix that is defined by a series of interwoven 12-membered ring hydrogen bonds (“12-helix”). Each hydrogen bond links a carbonyl oxygen to an amide proton three residues toward the C-terminus. CD data suggest that the conformational preference of trans-ACPC oligomers in methanol is strongly length-dependent, which implies that 12-helix formation is a cooperative process, as seen for the α-helix formed by conventional peptides. Previous work has established that oligomers and polymers of β-amino acids can adopt helical conformations, but the 12-helix is an unprecedented β-peptide secondary structure.

The preparation, crystal structures, and circular dichroism (CD) spectra of two oligomers of optically active trans-2-aminocyclohexanecarboxylic acid are reported. In the solid state, both the tetramer and the hexamer of this β-amino acid display a helical conformation that involves 14-membered-ring hydrogen bonds between a carbonyl oxygen and the amide proton of the second residue toward the N-terminus. (For comparison, the familiar α-helix observed in conventional peptides is associated with a 13-membered-ring hydrogen bond between a carbonyl oxygen and the amide proton of the fourth residue toward the C-terminus.) These crystallographic data, along with CD data obtained in methanol, suggest that the 14-helix constitutes a stable secondary structure for β-amino acid oligomers (“β-peptides”). In addition, the crystal packing pattern observed for the hexamer offers a blueprint for the design of β-peptides that might adopt a helical bundle tertiary structure.

No abstract

Many cellular processes are controlled by protein-protein interactions, and selective inhibition of these interactions could lead to the development of new therapies for several diseases. In the area of cancer, overexpression of the protein, human double minute 2 (HDM2), which binds to and inactivates the protein p53, has been linked to tumor aggressiveness and drug resistance. In general, inhibition of protein-protein interactions with synthetic molecules is challenging and currently remains a largely uncharted area for drug development. One strategy to create inhibitors of protein-protein interactions is to recreate the three-dimensional arrangement of side chains that are involved in the binding of one protein to another, using a nonnatural scaffold as the attachment point for the side chains. In this study, we used oligomeric peptoids as the scaffold to begin to develop a general strategy in which we could rationally design synthetic molecules that can be optimized for inhibition of protein-protein interactions. Structural information on the HDM2-p53 complex was used to design our first class of peptoid inhibitors, and we provide here, in detail, the strategy to modify peptoids with the appropriate side chains that are effective inhibitors of HDM2-p53 binding. While we initially tried to develop rigid, helical peptoids as HDM2 binders, the best inhibitors were surprisingly peptoids that lacked any helix-promoting groups. These results indicate that starting with rigid peptoid scaffolds may not always be optimal to develop new inhibitors.

No abstract

The conformational properties of β-peptides comprised of enantiomerically pure trans-2-aminocyclohexanecarboxylic acid (ACHC) or trans-2-aminocyclopentanecarboxylic acid (ACPC) units were studied by NMR spectroscopy in organic solvents. In pyridine-d 5 solution, ACPC hexamer 1 and ACPC octamer 2 displayed well-defined helical structures characterized by a series of 12-membered hydrogen-bonded rings (“12-helix”). The solution structures calculated from the NMR-derived constraints were very similar to the conformations found previously for 1 and 2 in the solid state. ACHC tetramer 3 displayed a different sort of helical conformation, characterized by a series of 14-membered hydrogen-bonded rings (“14-helix”), in methanol-d 3 solution. This solution conformation is similar to that previously found in the crystal structure of 3.