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Conformational Stability!?: Synthesis and Conformational Studies of Unnatural Backbone Modified Peptides
Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Kemiska institutionen, Avdelningen för organisk kemi.
2006 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
Abstract [en]

The beauty of the wide functionality of proteins and peptides in Nature is determined by their ability to adopt three-dimensional structures. This thesis describes artificial molecules developed to mimic secondary structures similar to those found crucial for biological activities.

In the first part of this thesis, we focused on post-translational modifications of a class of unnatural oligomers known as β-peptides. Through the design and synthesis of a glycosylated β3-peptide, the first such hybrid conjugate was reported. In this first report, a rather unstable 314-helical structure was found. Subsequently, a collection of six new glycosylated β3-peptides was synthesized with the aim to optimize the helical stability in water.

The ability of natural proteins, i.e. lectins, to recognize the carbohydrate residue on these unnatural peptide backbones was investigated through a biomolecular recognition study.

The second part of this thesis concerns the design of conformationally homogeneous scaffolds, which could be of importance for biomedical applications. In paper V, four- and five-membered cyclic all-β3-peptides were investigated for this purpose. In a subsequent paper, a completely different strategy was employed; herein, the ability of a single β2-amino acid to restrict the conformational freedom of a cyclic α-peptide was studied.

In the third part of this thesis, we synthesized and investigated the folding propensities of novel backbone modified oligomers, i.e. β-peptoids (N-substituted β-Ala) with α-chiral side chains.

The collective results of these studies have established the procedures required for synthesis of glycosylated β-peptides and deepened our understanding of the factors governing folding among such oligomers. Moreover, it was established that β-amino acids can be a useful tool to increase conformational stability of cyclic peptides.

sted, utgiver, år, opplag, sider
Uppsala: Acta Universitatis Upsaliensis , 2006. , s. 78
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 253
Emneord [en]
Organic chemistry, Conformational investigations, β-peptides, glycosylation, biomolecular recognition, cyclic β³-peptides, cyclic mixed α/β²-peptides, β-peptoids
Emneord [sv]
Organisk kemi
Identifikatorer
URN: urn:nbn:se:uu:diva-7420ISBN: 91-554-6759-8 (tryckt)OAI: oai:DiVA.org:uu-7420DiVA, id: diva2:169444
Disputas
2007-01-13, B42, BMC, Husargatan 3, Uppsala, 10:15
Opponent
Veileder
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22bibliografisk kontrollert
Delarbeid
1. Glycosylated Foldamers: Synthesis of Carbohydrate-modified β3hSer and Incorporation into β-Peptides
Åpne denne publikasjonen i ny fane eller vindu >>Glycosylated Foldamers: Synthesis of Carbohydrate-modified β3hSer and Incorporation into β-Peptides
2007 (engelsk)Inngår i: Journal of Peptide Science, ISSN 1075-2617, E-ISSN 1099-1387, Vol. 13, nr 11, s. 717-727Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Fmoc-protected β3hserine (β3hSer) was prepared and O-linked to suitably protected N-acetylgalactosamine (GalNAc) and N-acetylglucosamine (GlcNAc) derivatives. Glycosylation of β3hSer was made by two independent routes: either by direct glycosyl linkage to the β3hSer, or linkage to natural L-Ser and then utilizing the carbohydrate moiety as a protecting group in an Arndt–Eistert homologation. Both procedures gave the novel glycosylated β3-amino acids Fmoc-β3hSer(α-D-GalNAc(Ac)3)-OH (1a), its β-anomer (1b), and Fmoc-β3hSer(β-D-GlcNAc(Ac)3)-OH (2), which were utilized in the solid-phase peptide synthesis of four glycosylated dipeptides (3a–d) and two heptapeptides (4a–b). The preparation of β-amino acids bearing common post-translational modifiers represents an important step towards functionalized foldamers with broad applications in biomedical research.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-95278 (URN)10.1002/psc.832 (DOI)000252622900004 ()17890640 (PubMedID)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22 Sist oppdatert: 2017-12-14bibliografisk kontrollert
2. Functionalized foldamers: synthesis and characterization of a glycosylated β-peptide 314-helix conveying the Tn-antigen
Åpne denne publikasjonen i ny fane eller vindu >>Functionalized foldamers: synthesis and characterization of a glycosylated β-peptide 314-helix conveying the Tn-antigen
2005 Inngår i: Organic & Biomolecular Chemistry, ISSN 1477-0520, Vol. 3, nr 8, s. 1359-1361Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-95279 (URN)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22bibliografisk kontrollert
3. Glycosylated β3-Peptides: Relationship Between Peptide Sequence and 314-Helical Stability in Water
Åpne denne publikasjonen i ny fane eller vindu >>Glycosylated β3-Peptides: Relationship Between Peptide Sequence and 314-Helical Stability in Water
Artikkel i tidsskrift (Fagfellevurdert) Submitted
Identifikatorer
urn:nbn:se:uu:diva-95280 (URN)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22bibliografisk kontrollert
4. Biomolecular Recognition of Glycosylated β3-Peptides by GalNAc Specific Lectins
Åpne denne publikasjonen i ny fane eller vindu >>Biomolecular Recognition of Glycosylated β3-Peptides by GalNAc Specific Lectins
2007 (engelsk)Inngår i: Journal of Molecular Recognition, ISSN 0952-3499, E-ISSN 1099-1352, Vol. 20, nr 2, s. 132-138Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The molecular recognition of a novel kind of hybrid conjugates, composed of artificial biomimetic β-peptide oligomers with an O-linked natural N-acetyl-galactosamine (the Tn-antigen) residue, by four different GalNAc specific lectins was investigated using surface plasmon biosensor technology. The influence of the peptide and the glycosyl moiety on the recognition was studied using two glycosylated β3-heptapeptides, a glycosylated α-heptapeptide, two β-amino acid containing dipeptides, and monomeric αGalNAc-O-Thr. Although all four lectins displayed a decreased affinity for the carbohydrate residue when attached to a peptide, as compared to the monomeric Tn-antigen, the peptide part was found to have distinct effects on the binding kinetics - indicating that varying degrees of protein-peptide interactions occurred in the recognition process. Likewise, the lectins did not discriminate between β3-peptides and the α-peptide, but the β- linkage of the galactose had a detrimental effect for at least two of the lectins.

Emneord
b-peptides, glycopeptides, lectins, molecular recognition, surface plasmon resonance
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-95281 (URN)10.1002/jmr.821 (DOI)000246169000008 ()17410519 (PubMedID)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22 Sist oppdatert: 2017-12-14bibliografisk kontrollert
5. Cyclic β-tetra- and pentapeptides: Synthesis through on-resin cyclization and conformational studies by X-ray, NMR and CD spectroscopy and theoretical calculations
Åpne denne publikasjonen i ny fane eller vindu >>Cyclic β-tetra- and pentapeptides: Synthesis through on-resin cyclization and conformational studies by X-ray, NMR and CD spectroscopy and theoretical calculations
Vise andre…
2005 Inngår i: Chemistry--A European Journal, ISSN 0947-6539, Vol. 11, nr 21, s. 6145-6158Artikkel i tidsskrift (Fagfellevurdert) Published
Identifikatorer
urn:nbn:se:uu:diva-95282 (URN)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22bibliografisk kontrollert
6. β2-Amino Acids in the Design of Conformationally Homogeneous cyclo-Peptide Scaffolds
Åpne denne publikasjonen i ny fane eller vindu >>β2-Amino Acids in the Design of Conformationally Homogeneous cyclo-Peptide Scaffolds
Vise andre…
2006 (engelsk)Inngår i: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, nr 18, s. 6814-6821Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Herein, we report studies on the influence of chiral, beta(2)-amino acids in the design of conformationally homogeneous cyclic tetrapeptide scaffolds. The cyclic alpha-tetrapeptide cyclo(-Phe-D-Pro-Lys-Phe-) (1) and its four mixed analogues, having one of the alpha-Phe replaced by either an (S)-or an (R)-beta(2)hPhe residue (i.e., cyclo(-(R)-beta(2)hPhe-D-Pro-Lys-Phe) (2a), cyclo(-(S)-beta(2)hPhe-D-Pro-Lys-Phe-) (2b), cyclo(-Phe-D-Pro-Lys-(R)-beta(2)hPhe-) (3a), and cyclo(- Phe- D- Pro- Lys-( R)-, 2hPhe-) ( 3b)), were all synthesized through solidphase procedures followed by solution- phase cyclization. Initially, all five cyclo- peptides were analyzed by H-1 NMR spectroscopic studies in different solvents and at variable temperatures. Subsequently, a detailed 2D NMR spectroscopic analysis of three of the mixed peptides in water was performed, and the information thus extracted was used as restraints in a computational study on the peptides' conformational preference. An X- ray crystallographic study on the side chain- protected (Boc) 2a revealed the solid- state structure of this peptide. The results presented herein, together with previous literature data on beta(3)-amino acid residues, conclusively demonstrate the potential of beta-amino acids in the design of conformationally homogeneous cyclic peptides that are homologous to peptides with known applications in biomedicinal chemistry and as molecular receptors.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-95283 (URN)10.1021/jo060854n (DOI)000240020100013 ()16930031 (PubMedID)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22 Sist oppdatert: 2017-12-14bibliografisk kontrollert
7. Synthesis and circular dichroism spectroscopic investigations of oligomeric β-peptoids with α-chiral side chains
Åpne denne publikasjonen i ny fane eller vindu >>Synthesis and circular dichroism spectroscopic investigations of oligomeric β-peptoids with α-chiral side chains
2006 (engelsk)Inngår i: Organic Letters, ISSN 1523-7060, E-ISSN 1523-7052, Vol. 8, nr 20, s. 4533-4536Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Biomimetic oligomers are of large interest both as targets for combinatorial and parallel synthetic efforts and as foldamers. For example, shorter peptoid derivatives of beta-peptides, i.e., oligo-N-substituted beta-Ala, have been described as potential lead structures. Herein, we describe a solid-phase synthetic route to beta-peptoids with alpha-chiral aromatic N-substituents up to 11 residues long. Furthermore, the folding propensities of these oligomers were investigated by circular dichroism (CD) spectroscopy.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-95284 (URN)10.1021/ol061717f (DOI)000240654700038 ()16986943 (PubMedID)
Tilgjengelig fra: 2006-12-22 Laget: 2006-12-22 Sist oppdatert: 2017-12-14bibliografisk kontrollert

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