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postgraduate thesis: Synthesis, characterization and application of constrained 7/8 helix

TitleSynthesis, characterization and application of constrained 7/8 helix
Authors
Advisors
Advisor(s):Yang, D
Issue Date2010
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Shi, F. [石峰]. (2010). Synthesis, characterization and application of constrained 7/8 helix. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4436322
AbstractIn this thesis, constrained 7/8 helix has been developed to enhance the stability of 7/8 helical structure in polar and aqueous solvents for biological application. The synthesis of constrained 7/8 helical peptides has been achieved in two steps. In the first step, a 7/8 helical peptide chain comprising alternating α-L-amino acids and α-D-aminoxy acids was assembled by standard solution phase peptide synthesis protocol. In the second step, a covalent cross-linker as the conformational constraint was incorporated into 7/8 helical peptide at adjacent α-amino acid residues by consecutive intramolecular ring-closing olefin metathesis reaction and catalytic hydrogenation reaction. Conformational properties of constrained 7/8 helical peptides have been explored by applying NMR spectroscopy, theoretical calculation, and circular dichroism spectroscopy to three constrained tetrapeptides 2.2–2.4 and one non-cross-linked reference peptide 2.1. It was discovered that constrained 7/8 helical peptides with a saturated methylene chain as the covalent cross-linker maintained the structural feature of alternating N–O turns and γ-turns, and exhibited increased stability in both organic solvents and aqueous media. No obvious difference was observed for the covalent cross-linker with six, seven, or eight methylene units in improving the stability of 7/8 helix. The constrained 7/8 helix with enhanced structural stability was applied in the design of α-helix mimics. Based on the structure of helix D in the crystal structure of CD81 large extracellular loop, the putative receptor of Hepatitis C Virus envelop 2 (HCV E2) protein, constrained 7/8 helical hexapeptides 4.1 and 4.2 with free N-terminus were designed and synthesized in the form of TFA salt as the candidates of helix D mimics. It was expected that peptides 4.1 and 4.2 could act as the inhibitors of the interaction between helix D and HCV E2 to block HCV entry into cells. Unfortunately, the biological activity test on the ability of peptides 4.1 and 4.2 in HCV inhibition revealed that none of these peptides exhibited detectable inhibitory effect on the entry of HCV into cells and HCV replication at the concentration of 100 μM.
DegreeDoctor of Philosophy
SubjectPeptides.
Dept/ProgramChemistry

 

DC FieldValueLanguage
dc.contributor.advisorYang, D-
dc.contributor.authorShi, Feng-
dc.contributor.author石峰-
dc.date.issued2010-
dc.identifier.citationShi, F. [石峰]. (2010). Synthesis, characterization and application of constrained 7/8 helix. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR. Retrieved from http://dx.doi.org/10.5353/th_b4436322-
dc.description.abstractIn this thesis, constrained 7/8 helix has been developed to enhance the stability of 7/8 helical structure in polar and aqueous solvents for biological application. The synthesis of constrained 7/8 helical peptides has been achieved in two steps. In the first step, a 7/8 helical peptide chain comprising alternating α-L-amino acids and α-D-aminoxy acids was assembled by standard solution phase peptide synthesis protocol. In the second step, a covalent cross-linker as the conformational constraint was incorporated into 7/8 helical peptide at adjacent α-amino acid residues by consecutive intramolecular ring-closing olefin metathesis reaction and catalytic hydrogenation reaction. Conformational properties of constrained 7/8 helical peptides have been explored by applying NMR spectroscopy, theoretical calculation, and circular dichroism spectroscopy to three constrained tetrapeptides 2.2–2.4 and one non-cross-linked reference peptide 2.1. It was discovered that constrained 7/8 helical peptides with a saturated methylene chain as the covalent cross-linker maintained the structural feature of alternating N–O turns and γ-turns, and exhibited increased stability in both organic solvents and aqueous media. No obvious difference was observed for the covalent cross-linker with six, seven, or eight methylene units in improving the stability of 7/8 helix. The constrained 7/8 helix with enhanced structural stability was applied in the design of α-helix mimics. Based on the structure of helix D in the crystal structure of CD81 large extracellular loop, the putative receptor of Hepatitis C Virus envelop 2 (HCV E2) protein, constrained 7/8 helical hexapeptides 4.1 and 4.2 with free N-terminus were designed and synthesized in the form of TFA salt as the candidates of helix D mimics. It was expected that peptides 4.1 and 4.2 could act as the inhibitors of the interaction between helix D and HCV E2 to block HCV entry into cells. Unfortunately, the biological activity test on the ability of peptides 4.1 and 4.2 in HCV inhibition revealed that none of these peptides exhibited detectable inhibitory effect on the entry of HCV into cells and HCV replication at the concentration of 100 μM.-
dc.languageeng-
dc.publisherThe University of Hong Kong (Pokfulam, Hong Kong)-
dc.relation.ispartofHKU Theses Online (HKUTO)-
dc.rightsThe author retains all proprietary rights, (such as patent rights) and the right to use in future works.-
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.source.urihttp://hub.hku.hk/bib/B44363229-
dc.subject.lcshPeptides.-
dc.titleSynthesis, characterization and application of constrained 7/8 helix-
dc.typePG_Thesis-
dc.identifier.hkulb4436322-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChemistry-
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.5353/th_b4436322-
dc.date.hkucongregation2010-

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