Design of Peptidic Foldamer Helices: A Stereochemical Patterning Approach

Mándity, István M.; Wéber, Edit; Martinek, Tamás A.; Olajos, Gábor; Tóth, Gábor; Vass, Elemér; Fülöp, Ferenc

doi:10.1002/ange.200805095

Cited by 49 publications

(40 citation statements)

References 58 publications

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“…The relationship between the chirality of substitution and folding preference was studied by several groups (Günther 2001;Beke et al 2006a;Seebach et al 1999;Möhle et al 1999;Wu and Wang 1998;Günther and Hofmann 2002;Martinek et al 2002;Mandity et al 2009). Oligomers composed of one to six residues of b-Ala, Fig.…”

Section: Introductionmentioning

confidence: 99%

“…More recently, a systematic study on oligomers of b-amino acids containing five membered rings was carried out (Mandity et al 2009). For these structures, a general folding rule was proposed: homochiral models (u and w torsional angles having the same sign) form helices, while heterochiral models (u and w torsional angles having opposite sign) form strand structures.…”

Section: Introductionmentioning

confidence: 99%

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Exploiting diverse stereochemistry of β-amino acids: toward a rational design of sheet-forming β-peptide systems

et al. 2011

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Due to the two methylene groups in their backbone, b-amino acids can adopt numerous secondary structures, including helices, sheets and nanotubes. Chirality introduced by the additional side chains can significantly influence the folding preference of b-peptides composed of chiral b-amino acids. However, only conceptual suggestions are present in the literature about the effect of chirality on folding preferences. Summarizing both the experimental and computational results, Seebach (Chem Biodivers 1: 2004) has proposed the first selection rule on the effect of side chain chirality, on the folding preference of b-peptides. In order to extend and fine-tune the aforementioned predictions of Seebach, we have investigated its validity to the novel type of apolar sheet proposed recently (Pohl et al. in J Phys Chem B 114:9338-9348, 2010). In order to facilitate the rational design of sheet-like structures, a systematic study on the effect of chirality on ''apolar'' sheet stability is presented on disubstituted [HCO-b-Ala-b 2,3 -hAla-b-Ala-NH 2 ] 2 model peptides calculated at the M05-2X/6-311??G(d,p)//M05-2X/6-31G(d) and B3LYP/6-311??G(d,p)//B3LYP/6-31G(d) levels of theory both in vacuum and in polar and apolar solvents. In addition, both types of ''apolar'' sheets were investigated; the one with two strands of identical (AA) and enantiomeric (AB) backbone structure. Our results show that heterochirally disubstituted sheets have the greatest preference for sheet formation (DG * -11 kcal mol -1 ). However, in contrast to Seebach's predictions, ''homochiral disubstitution'' itself does not necessarily disrupt the sheet structure, rather it could result stable fold (DG * -5 kcal mol -1 ). Results indicate that both the methyl group orientation and the local conformational effect of substitution affects sheet stability, as point chirality was found to have influence only on the backbone torsional angles. These results enabled us to extend and generalize Seebach's predictions and to propose a more general and accurate ''rule of thumb'' describing the effect of chirality on sheet stability. This offers an easy-to-use summary on how to design b-peptide sheet structures. We conclude that heterochirally disubstituted models are the best candidates for sheet formation, if the two strands are substituted in a way to create identical torsional angle sets on the two backbones for ideal hydrogen-bonding pattern. With adequately selected side chains, homochirally disubtituted derivatives may also form sheet structures, and the position of methyl groups would prevent assembly of more than two strands making it ideal to create hairpins.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploiting diverse stereochemistry of β-amino acids: toward a rational design of sheet-forming β-peptide systems

et al. 2011

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“…[4,8] As regards the synthesis of peptidomimetics and glycomimetics derived from α-AAs, acyclic or cyclic -AAs [e.g., ACPC (2-aminocyclopentane-1-carboxylic acid) [9,10] and ACHC (2aminocyclohexane-1-carboxylic acid) [11,12] ], and -SAAs, we have completed the synthesis of selected 3-amino-3-deoxypentofuranuronic acids, [13] and studied their coupling potential to form peptidosaccharides. The corresponding pyranoid SAAs have seldom been used to make foldamers, as the building blocks are unavailable.…”

Section: Introductionmentioning

confidence: 99%

Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

et al. 2018

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Pyranuronic β‐sugar amino acids (β‐SAAs) are biocompatible and tuneable building blocks of foldamers and chimera‐peptides. The scalable and economical total synthesis of two building blocks is described here. These C‐4 epimers, Fmoc‐GlcAPU(Me)‐OH (7) and Fmoc‐GalAPU(Me)‐OH (8), which are suitable for solid phase peptide synthesis, were prepared via a common oxime intermediate 16. The new synthesis uses nine consecutive steps, starting from methyl α‐d‐glucopyranoside (6). The synthesis is fine‐tuned, optimized, and ready for large‐scale and cost‐efficient production.

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“…The secondary structure and self-assembly of peptidic foldamers can be controlled via the β-amino acid sequence and backbone stereochemistry, 150 and also tuned via the side-chain chemistry. 151 Moreover, their resistance to enzymatic degradation has been demonstrated, [152][153][154] which is a very important feature for a drug scaffold. Protein and α-peptide sequences are designated by using the standard one-letter amino acid codes.…”

Section: Foldamers As Drug Candidates For Difficult Targetsmentioning

confidence: 99%

Investigation of protein–ligand interactions of targets with solvent exposed binding sites

Wéber

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Design of Peptidic Foldamer Helices: A Stereochemical Patterning Approach

Abstract: Klares Konstruktionsprinzip: Die programmierten Sequenzen von stereochemischen Bausteinen führen zu neuartigen biomimetischen Helices. Dieser rationale Ansatz eröffnet neue Möglichkeiten beim Aufbau periodischer Sekundärstrukturen.magnified image

Cited by 49 publications

References 58 publications

Exploiting diverse stereochemistry of β-amino acids: toward a rational design of sheet-forming β-peptide systems

Exploiting diverse stereochemistry of β-amino acids: toward a rational design of sheet-forming β-peptide systems

Approaches to Pyranuronic β‐Sugar Amino Acid Building Blocks of Peptidosaccharide Foldamers

Investigation of protein–ligand interactions of targets with solvent exposed binding sites

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