An unnatural amino acid that induces β-sheet folding and interaction in peptides

James S. Nowick, Kit Lam, Tatyana V. Khasanova, William E. Kemnitzer, Santanu Maitra, Hao T. Mee, Ruiwu Liu

Research output: Contribution to journalArticle

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Abstract

This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into β-sheetlike structures that dimerize through β-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the β-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a β-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe·TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric β-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces β-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a β-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of β-sheet structure with minimal perturbation of the peptide sequence.

Original languageEnglish (US)
Pages (from-to)4972-4973
Number of pages2
JournalJournal of the American Chemical Society
Volume124
Issue number18
DOIs
StatePublished - May 8 2002

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Peptides
Amino acids
Amino Acids
Coupling agents
Dacarbazine
Ornithine
Nuclear magnetic resonance
N(delta)-((3-(((isopropylamino)hydrazino)carbonyl)-4-methylphenyl)aminooxalyl)ornithine
Solid-Phase Synthesis Techniques
Splints
Chemical shift
Prosthetics
Organic solvents
Conformations
Hydrogen
Hydrogen bonds
Salts
Derivatives

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Nowick, J. S., Lam, K., Khasanova, T. V., Kemnitzer, W. E., Maitra, S., Mee, H. T., & Liu, R. (2002). An unnatural amino acid that induces β-sheet folding and interaction in peptides. Journal of the American Chemical Society, 124(18), 4972-4973. https://doi.org/10.1021/ja025699i

An unnatural amino acid that induces β-sheet folding and interaction in peptides. / Nowick, James S.; Lam, Kit; Khasanova, Tatyana V.; Kemnitzer, William E.; Maitra, Santanu; Mee, Hao T.; Liu, Ruiwu.

In: Journal of the American Chemical Society, Vol. 124, No. 18, 08.05.2002, p. 4972-4973.

Research output: Contribution to journalArticle

Nowick, JS, Lam, K, Khasanova, TV, Kemnitzer, WE, Maitra, S, Mee, HT & Liu, R 2002, 'An unnatural amino acid that induces β-sheet folding and interaction in peptides', Journal of the American Chemical Society, vol. 124, no. 18, pp. 4972-4973. https://doi.org/10.1021/ja025699i
Nowick, James S. ; Lam, Kit ; Khasanova, Tatyana V. ; Kemnitzer, William E. ; Maitra, Santanu ; Mee, Hao T. ; Liu, Ruiwu. / An unnatural amino acid that induces β-sheet folding and interaction in peptides. In: Journal of the American Chemical Society. 2002 ; Vol. 124, No. 18. pp. 4972-4973.
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abstract = "This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into β-sheetlike structures that dimerize through β-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the β-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a β-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe·TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric β-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces β-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a β-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of β-sheet structure with minimal perturbation of the peptide sequence.",
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T1 - An unnatural amino acid that induces β-sheet folding and interaction in peptides

AU - Nowick, James S.

AU - Lam, Kit

AU - Khasanova, Tatyana V.

AU - Kemnitzer, William E.

AU - Maitra, Santanu

AU - Mee, Hao T.

AU - Liu, Ruiwu

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N2 - This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into β-sheetlike structures that dimerize through β-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the β-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a β-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe·TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric β-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces β-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a β-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of β-sheet structure with minimal perturbation of the peptide sequence.

AB - This paper introduces a unique amino acid that can readily be incorporated into peptides to make them fold into β-sheetlike structures that dimerize through β-sheet interactions. This new amino acid, Orn(i-PrCO-Hao), consists of an ornithine residue with the β-strand-mimicking amino acid Hao [J. Am. Chem. Soc. 2000, 122, 7654-7661] attached to its side chain. When Orn(i-PrCO-Hao) is incorporated into a peptide, or appended to its N-terminus, the Hao group hydrogen bonds to the three subsequent residues to form a β-sheetlike structure. The amino acid Orn(i-PrCO-Hao) is readily used in peptide synthesis as its Fmoc derivative, Fmoc-Orn(i-PrCO-Hao)-OH (3). Fmoc-Orn(i-PrCO-Hao)-OH behaves like a regular amino acid in peptide synthesis and was uneventfully incorporated into the peptide o-anisoyl-Val-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe (4) through standard automated Fmoc solid-phase peptide synthesis, with DIC and HOAt as the coupling agent for Fmoc-Orn(i-PrCO-Hao)-OH and o-anisic acid and HATU as the coupling agent for all other couplings. A second synthetic strategy was developed to facilitate the preparation of peptides with N-terminal Orn(i-PrCO-Hao) residues, which avoids the need for the preparation of Fmoc-Orn(i-PrCO-Hao)-OH. In this strategy, Boc-Orn(Fmoc)-OH is used as the penultimate amino acid in the peptide synthesis, and i-PrCO-Hao-OH (2) is used as the final amino acid. N-Terminal Orn(i-PrCO-Hao) peptide H-Orn(i-PrCO-Hao)-Phe-Ile-Leu-NHMe·TFA (5) was prepared in a fashion similar to that for 4, using DIC and HOAt as the coupling agent for i-PrCO-Hao-OH and HATU as the coupling agent for all other couplings. 1H NMR transverse-ROESY, coupling constant, and chemical shift studies establish that peptide 4 forms a dimeric β-sheetlike structure in CDCl3 solution. The 1H NMR studies also suggest that the ornithine unit adopts a well-defined turn conformation. Analogous 1H NMR studies of peptide 5 indicate that this TFA salt folds but does not dimerize in CD3OD solution. Collectively, these synthetic and spectroscopic studies establish that the amino acid Orn(i-PrCO-Hao) induces β-sheet structure and interactions in peptides in suitable organic solvents. Unlike the Hao amino acid, which acts as a prosthetic to replace three residues of the peptide strand, the Orn(i-PrCO-Hao) amino acid acts as a splint that helps enforce a β-sheetlike structure without replacing the residues and their side chains. This feature of Orn(i-PrCO-Hao) is important, because it allows the creation of β-sheet structure with minimal perturbation of the peptide sequence.

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