Side chain-to-Side chain Cyclization by Intramolecular Click Reaction - Building Blocks, Solid Phase Synthesis and Conformational Characterization

Cantel, Sonia; Halperin, José A.; Chorev, Michael; Scrima, Mario; D’Ursi, Anna Maria; Levy, Jay J.; DiMarchi, Richard D.; Chevalier, Alexandra Le; Rovero, Paolo; Papini, Anna Maria

doi:10.1007/978-0-387-73657-0_80

Cited by 4 publications

(3 citation statements)

References 4 publications

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“…By substitution of one (2)(3)(4), two (5), or all three (6 and 7) positions, we generated peptides with increasingly marked differences in the (1, 4, 7)-hydrophobic pattern with respect to 1Y: For example, the analog with highest similarity to 1Y is represented by 2 that contains norleucine-4 (Nle-4) in place of Leu-4, followed by analogs 3 and 4, in which Leu-4 or Leu-7 was replaced by the sterically more demanding Tyr-4 or Ile-7, respectively (Figure 1C). In addition, we prepared three analogs, in which also position 9 was changed (8)(9)(10). The peptides containing two up to four substitutions are more different from 1Y, except for analog 7 that contains three norleucine residues in place of Val-1, Leu-4, and Leu-7: Indeed, only the substitution Val1Nle (isopropyl versus n-butyl) can be considered less conservative.…”

Section: Modification Of the Hydrophobic Pattern Of 1ymentioning

confidence: 99%

“…The α‐helix represents one of the most common secondary structures of bioactive peptides and protein domains, and helical motifs often play a key role in important molecular recognition events. 1 , 2 In order to augment the helicity of short sequences involved in ligand/protein or protein/protein interactions, a variety of covalent constraints have been developed, which include backbone H‐bond mimicry 3 , 4 and side‐chain crosslinking via disulfide, 5 sulfide, 6 , 7 1,4‐triazole, 8 , 9 hydrocarbon, 10 , 11 , 12 , 13 , 14 , 15 diester, 16 and lactam bridges. 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 These covalent constraints are also used in combination with unnatural amino acids that prefer the helical structure and/or may increase peptide stability against proteases, like Cα‐tetrasubstituted amino acids and β‐ and γ‐amino acids.…”

Section: Introductionmentioning

confidence: 99%

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Backbone distortions in lactam‐bridged helical peptides

Moazzam

Stanojlović

Hinterholzer

et al. 2022

Journal of Peptide Science

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Side‐chain‐to‐side‐chain cyclization is frequently used to stabilize the α‐helical conformation of short peptides. In a previous study, we incorporated a lactam bridge between the side chains of Lys‐i and Asp‐i+4 in the nonapeptide 1Y, cyclo‐(2,6)‐(Ac‐VKRLQDLQY‐NH2), an artificial ligand of the inhibitor of DNA binding and cell differentiation (ID) protein with antiproliferative activity on cancer cells. Herein, we show that only the cyclized five‐residue segment adopts a helical turn whereas the C‐terminal residues remain flexible. Moreover, we present nine 1Y analogs arising from different combinations of hydrophobic residues (leucine, isoleucine, norleucine, valine, and tyrosine) at positions 1, 4, 7, and 9. All cyclopeptides except one build a lactam‐bridged helical turn; however, residue‐4 reveals less helix character than the neighboring Arg‐3 and Gln‐5, especially with residue‐4 being isoleucine, valine, and tyrosine. Surprisingly, only two cyclopeptides exhibit helix propagation until the C‐terminus, whereas the others share a remarkable outward tilting of the backbone carbonyl of the lactam‐bridged Asp‐6 (>40° deviation from the orientation parallel to the helix axis), which prevents the formation of the H‐bond between Arg‐3 CO and residue‐7 NH: As a result, the propagation of the helix beyond the lactam‐bridged sequence becomes unfavorable. We conclude that, depending on the amino‐acid sequence, the lactam bridge between Lys‐i and Asp‐i+4 can stabilize a helical turn but deviations from the ideal helix geometry are possible: Indeed, besides the outward tilting of the backbone carbonyls, the residues per turn increased from 3.6 (typical of a regular α‐helix) to 4.2, suggesting a partial helix unwinding.

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Section: Modification Of the Hydrophobic Pattern Of 1ymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Backbone distortions in lactam‐bridged helical peptides

Moazzam

Stanojlović

Hinterholzer

et al. 2022

Journal of Peptide Science

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“…Therefore, many efforts are made to mimic interacting α-helices and use them for the modulation of protein interactions involving α-helices [3][4][5][6][7][8][9][10][11]. Several approaches can be used to stabilize the helical conformation of a short peptide sequence: Some of these are based on metal ion chelation [12,13], helix-nucleating templates [14][15][16], hydrogen bond surrogates [17,18], non-covalent side chain constraints [19,20] and covalent side chain linkages such as the disulfide [21], thioether [22,23], triazole [24,25], hydrocarbon [7,9,10,[26][27][28], diester [29], and lactam bridges [30][31][32][33][34][35][36][37][38]. Alternatively or in combination with covalent constraints, unnatural amino acids with preference for the helical structure can be used, like Cα-tetrasubstituted, β-, and γ-amino acids [4,5,28,29,39].…”

Section: Introductionmentioning

confidence: 99%

Impact of the amino acid sequence on the conformation of side chain lactam‐bridged octapeptides

Neukirchen

Krieger

Roschger

et al. 2017

Journal of Peptide Science

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Synthetic helical peptides are valuable scaffolds for the development of modulators of protein-protein interactions involving helical motifs. Backbone-to-side chain or side chain-to-side chain constraints have been and still are intensively exploited to stabilize short α-helices. Very often, these constraints have been combined with backbone modifications induced by Cα-tetrasubstituted, β-, or γ-amino acids, which facilitate the α-peptide or α/β/γ-peptide adopting an α-helical conformation. In this work, we investigated the helical character of octapeptides that were cyclized by a Lys-Asp-(i,i + 4)-lactam bridge. We started with two sequences extracted from the helix-loop-helix region of the Id proteins, which are inhibitors of cell differentiation during development and in cancer. Nineteen analogs containing the lactam bridge at different positions and displaying different amino acid core triads (i + 1,2,3) as well as outer residues were prepared by solid-phase methodology. Their conformation in water and water/2,2,2-trifluoroethanol mixtures was investigated by circular dichroism (CD) spectroscopy. The cyclopeptides could be grouped in helix-prone and non-helix-prone structures. Both the amino acid core triad (i + 1,2,3) and the pendant residues positively or negatively affected the formation of a helical structure. Computational studies based on the NMR-derived helical structure of a cyclopeptide containing Aib at position (i + 2) of the triad were generally in agreement with the secondary structure propensity of the cyclopeptides observed by CD spectroscopy. In conclusion, the Lys-Asp-(i,i + 4)-lactam bridge may succeed or fail in the stabilization of short helices, depending on the primary structure. Moreover, computational methods may be valuable tools to discriminate helix-prone from non-helix-prone peptide-based macrolactams. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.

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Discovery of a Robust and Efficient Homogeneous Silver(I) Catalyst for the Cycloaddition of Azides onto Terminal Alkynes

2012

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A highly efficient, chemically stable, and well‐defined homogeneous silver(I) catalyst is reported for the cycloaddition of azides onto terminal alkynes (Ag‐AAC reaction). The Ag‐AAC reaction occurs at room temperature or with heating to deliver exclusively the corresponding 1,4‐triazole. A pronounced ligand effect was discovered through systematic modification to the ligand structure resulting in the discovery of a chemically stable active catalyst for this reaction.

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Side chain-to-Side chain Cyclization by Intramolecular Click Reaction - Building Blocks, Solid Phase Synthesis and Conformational Characterization

Cited by 4 publications

References 4 publications

Backbone distortions in lactam‐bridged helical peptides

Backbone distortions in lactam‐bridged helical peptides

Impact of the amino acid sequence on the conformation of side chain lactam‐bridged octapeptides

Discovery of a Robust and Efficient Homogeneous Silver(I) Catalyst for the Cycloaddition of Azides onto Terminal Alkynes

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