Efficient helix nucleation by a macrocyclic triproline-derived template

Kemp, D. S.; Rothman, Jeffrey H.

doi:10.1016/0040-4039(95)00707-j

Cited by 16 publications

(19 citation statements)

References 6 publications

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“…Thus, distances to these protons are independent of side-chain rotamer distributions and consequently predictable for specific conformations. Since α-helices are characterized by a unique pattern of short, sequential distances d αβ ( i , i + 3), alanine-based peptides can be used to test for the α-helical conformation on a per residue basis 20e. Although NMR signals for alanine often overlap, they can be edited and assigned by means of deuterated alanine analogues 20e.…”

Section: Designmentioning

confidence: 99%

“…Since α-helices are characterized by a unique pattern of short, sequential distances d αβ ( i , i + 3), alanine-based peptides can be used to test for the α-helical conformation on a per residue basis 20e. Although NMR signals for alanine often overlap, they can be edited and assigned by means of deuterated alanine analogues 20e. A second constrained peptide, [ J LP Z ]AEAAKA-NH 2 ( 3 ), was synthesized to test whether l -proline with φ = −60°,15d close to the ideal for an α-helix ( φ = −57°), could enhance α-helix stabilization.…”

Section: Designmentioning

confidence: 99%

“…Several synthetic approaches to helix stabilization have been taken . One approach builds on templates to propagate helices. ,, A second approach links amino acid side chains in a position-dependent manner to stabilize helices . A third approach uses linkers, bridges or synthetic scaffolds to position peptide chains in proximity for helix-stabilizing interactions …”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Hydrogen Bond Mimic Approach: Solid-Phase Synthesis of a Peptide Stabilized as an α-Helix with a Hydrazone Link

1999

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Proteins are characterized by extensive hydrogen bonding that defines regular and irregular substructures. However, hydrogen bonds are weak and insufficient for stabilizing peptide conformation in water. Consequently, the biological activity of peptides is reduced. This led us to test whether a covalent mimic of the hydrogen bond could be used to stabilize peptide conformation in water. A solid-phase synthesis is described for replacing a main-chain hydrogen bond (NH f OdCRNH) with a hydrazone link (N-Nd CH-CH 2 CH 2 ) in peptides. The synthesis is easy to implement, rapid, and capable of high yields. The replacement of a putative (i + 4 f i) hydrogen bond with the hydrazone at the N terminus of acetyl-GLAGAEAAKA-NH 2 (1) to give [JLAZ]AEAAKA-NH 2 (2) converts it to a full-length R-helix in water at ambient temperature as indicated by NMR spectroscopy. The observation of weak d RN (i, i + 3), medium d NN (i, i + 1), and strong d R (i, i + 3) NOEs that span 2 establish the formation of a full-length R-helix in water. J RN coupling constants and amide proton chemical shifts and temperature coefficients are consistent with a model involving rapidly equilibrating extended and R-helical conformers. Substituting L-alanine with L-proline to give [JLPZ]AEAAKA-NH 2 (3) enhances R-helix nucleation and shifts the equilibrium further toward full-length R-helix. The hydrazone link displays many of the properties required of a hydrogen bond mimic and could find use as a general means for constraining peptides to a range of biologically relevant conformations.

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Section: Designmentioning

confidence: 99%

Section: Designmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Hydrogen Bond Mimic Approach: Solid-Phase Synthesis of a Peptide Stabilized as an α-Helix with a Hydrazone Link

1999

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“…Kemp and co-workers synthesized template 1 to mimic the conformation of proline residues commonly found as N -terminal motifs in protein α-helices [27,28]. The pyrrolidine rings have a fixed ϕ value near −60°, which is close to the ideal helix value.…”

Section: N-terminal End-cap Strategiesmentioning

confidence: 99%

End-capped α-helices as modulators of protein function

Mahon

Arora

2012

Drug Discovery Today: Technologies

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Examination of complexes of proteins with other biomolecules reveals that proteins tend to interact with partners via folded sub-domains, in which the backbone possesses secondary structure. α-Helices, the largest class of protein secondary structures, play fundamental roles in a multitude of highly specific protein-protein and protein-nucleic acids interactions. Herein, we describe the potential of a helix nucleation strategy to afford modulators of protein-protein interactions.

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“…Last, synthetic agents have been shown to act as nucleators of helix formation. By providing rigidly constrained, appropriately placed hydrogen bonds to one end of a peptide, Kemp et al [ 69 , 70 ], Austin etal. [ 71 ], and Kazmierski et al [ 72 ] have all provided a means for nucleation of helicity.…”

Section: Stabilized and Destabilized α -Helicesmentioning

confidence: 99%