Intermolecular stabilisation of the β-sheet conformation in dipeptides

Schräder, Thomas; Kirsten, Christian

doi:10.1039/cc9960002089

Cited by 39 publications

(22 citation statements)

References 17 publications

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“…[21] A logical extension affords the first soluble β-sheet models, in which combinations of these artificial (Nowick [22] ) and natural (Kemp, [23] Feigel, [24] Kelly, [25] Gellman [26] ) peptide strands are attached to common scaffolds and interact along their inner faces like zippers to form two-or three-stranded parallel or antiparallel β-sheets. Very recently the first intermolecular versions of these β-sheet models were created (Schrader, [27] Hamil-ton, [28] Bartlett [29] ), albeit in organic solvents. Aminopyrazoles, diaminoquinolones and azacyclohexenones ( Figure 2) are thus all able to form the maximum number of possible hydrogen bonds to the top and bottom faces of an extended peptide strand backbone.…”

Section: Introductionmentioning

confidence: 99%

Sequence‐Selective Peptide Recognition with Designed Modules

et al. 2005

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A concept for the rational design of sequence‐selective peptide receptors has been extended: in addition to recognition modules for polar, aromatic and basic amino acids, the series has now been completed with new receptor units for apolar and acidic amino acids. The underlying strategy uses the intermolecular β‐sheet stabilization of a dipeptide as a prerequisite to bind its N‐terminal amino acid side chain through a strategically placed recognition tip at the end of a U‐turn protruding from the receptor moiety. Thus, a diaminopyrazole has been covalently attached to Kemp’s triacid by way of a cyclic imide, while a meta‐substituted aniline was coupled as an amide to the pendant third carboxylate arm, bringing the two aromatic units into a sub‐van der Waals distance in a tight conformational lock. NMR titrations, Karplus analyses and Monte‐Carlo simulations demonstrate the effective sequence‐selective recognition of alanine‐containing dipeptides. No example of such a rationally designed set of peptide receptors had existed previously. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

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Section: Introductionmentioning

confidence: 99%

Sequence‐Selective Peptide Recognition with Designed Modules

et al. 2005

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“…These rigid heterocyclic structures have been investigated in solution with respect to their backbone recognition abilities by various NMR and IR spectroscopic methods as well as by force-field calculations. [4][5][6][7][8] To successfully compete with peptide dimerization, such a ligand must form a peptide complex with a superior gain of free enthalpy. Many different factors, however, determine its overall affinity in solution, among others solvation energies and secondary structure stabilities of the peptide environment.…”

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Interactions of Small Protected Peptides with Aminopyrazole Derivatives: The Efficiency of Blocking a β‐Sheet Model in the Gas Phase

et al. 2009

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Binding motifs of aminopyrazole derivatives with different peptides in the gas phase are investigated by using mass‐ and isomer‐selective IR/UV spectroscopy. The efficiency of blocking a β‐sheet model is determined by analyzing the number and strength of hydrogen bonds (see picture). The investigations yield information on intrinsic molecular properties of beginning aggregation behavior, as might also occur in misfolding diseases.

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“…Simple ␤-sheet templates have also been incorporated into drugs that bind to a peptide region with ␤-sheet conformation (34). However, external templates, which force a peptide strand into the ␤-sheet conformation, are very rare (35)(36)(37). Meredith and co-workers (26,27) very recently demonstrated the paramount importance of backbone hydrogen bonding for the formation of ␤-amyloid fibrils; replacing the amide bonds by ester linkages completely eliminated any aggregation propensity of the respective peptide-like compound taken from the A␤ sequence (26,27).…”

Section: Concept Andmentioning

confidence: 99%

Prevention of Alzheimer's Disease-associated Aβ Aggregation by Rationally Designed Nonpeptidic β-Sheet Ligands

Rzepecki

Nagel-Steger

Feuerstein

et al. 2004

Journal of Biological Chemistry

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A new concept is introduced for the rational design of ␤-sheet ligands, which prevent protein aggregation. Oligomeric acylated aminopyrazoles with a donor-acceptor-donor (DAD) hydrogen bond pattern complementary to that of a ␤-sheet efficiently block the solvent-exposed ␤-sheet portions in A␤-(1-40) and thereby prevent formation of insoluble protein aggregates. Density gradient centrifugation revealed that in the initial phase, the size of A␤ aggregates was efficiently kept between the trimeric and 15-meric state, whereas after 5 days an additional high molecular weight fraction appeared. With fluorescence correlation spectroscopy (FCS) exactly those two, i.e. a dimeric aminopyrazole with an oxalyl spacer and a trimeric head-to-tail connected aminopyrazole, of nine similar aminopyrazole ligands were identified as efficient aggregation retardants whose minimum energy conformations showed a perfect complementarity to a ␤-sheet. The concentration dependence of the inhibitory effect of a trimeric aminopyrazole derivative allowed an estimation of the dissociation constant in the range of 10 ؊5 M. Finally, electrospray ionization mass spectrometry (ESI-MS) was used to determine the aggregation kinetics of A␤-(1-40) in the absence and in the presence of the ligands. From the comparable decrease in A␤ monomer concentration, we conclude that these ␤-sheet ligands do not prevent the initial oligomerization of monomeric A␤ but rather block further aggregation of spontaneously formed small oligomers. Together with the results from density gradient centrifugation and fluorescence correlation spectroscopy it is now possible to restrict the approximate size of soluble A␤ aggregates formed in the presence of both inhibitors from 3-to 15-mers.

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Intermolecular stabilisation of the β-sheet conformation in dipeptides

Cited by 39 publications

References 17 publications

Sequence‐Selective Peptide Recognition with Designed Modules

Sequence‐Selective Peptide Recognition with Designed Modules

Interactions of Small Protected Peptides with Aminopyrazole Derivatives: The Efficiency of Blocking a β‐Sheet Model in the Gas Phase

Prevention of Alzheimer's Disease-associated Aβ Aggregation by Rationally Designed Nonpeptidic β-Sheet Ligands

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