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postgraduate thesis: Total synthesis of teixobactin and its analogues and a novel desulfurization method for peptide and protein synthesis

TitleTotal synthesis of teixobactin and its analogues and a novel desulfurization method for peptide and protein synthesis
Authors
Advisors
Advisor(s):Li, XC
Issue Date2018
PublisherThe University of Hong Kong (Pokfulam, Hong Kong)
Citation
Jin, K. [金康]. (2018). Total synthesis of teixobactin and its analogues and a novel desulfurization method for peptide and protein synthesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.
AbstractThe problem of multidrug resistance has become increasingly serious due to the abuse of antibiotics. In order to treat infections by these so called “superbugs”, novel antibiotics are urgently needed for the clinic. Toward this end, a new and effective antibiotic, named teixobactin, was discovered in 2015 that showed promise as a new antibacterial lead. Teixobactin exhibits potent antibacterial activity against a series of Gram-positive pathogens, including drug-resistant bacteria such as vancomycin-resistant Enterococcus faecalis and faecium (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Mycobacterium tuberculosis (Mtb). Structurally, teixobactin contains a 13-membered depsipeptide ring consisting of 4 amino acids and a linear exocyclic tail made up of 7 amino acids. To conduct the medicinal chemistry study on teixobactin, we first engaged in the development of its total synthesis. In chapter 2, we adopted a convergent 6+5 strategy and successfully completed the total synthesis of teixobactin with serine ligation as the key step for the convergent synthesis. Meanwhile, a series of teixobactin analogues have been synthesized through the similar convergent method, which has allowed us to establish the structure-activity relationship to search for more promising antibacterial lead compounds. Cysteine-based native chemical ligation (NCL) is a widely used approach for peptide and protein chemical synthesis since its discovery by Kent and co-workers. However, the relative scarity of cysteine residues in naturally occurring proteins limits its widespread use. In chapter 3, we have developed a powerful P-B desulfurization strategy to expand the application of NCL-desulfurization. In addition, we have applied this novel method for the total syntheses of several natural peptides and proteins.
DegreeDoctor of Philosophy
SubjectPeptide antibiotics
Proteins - Synthesis
Dept/ProgramChemistry
Persistent Identifierhttp://hdl.handle.net/10722/267787

 

DC FieldValueLanguage
dc.contributor.advisorLi, XC-
dc.contributor.authorJin, Kang-
dc.contributor.author金康-
dc.date.accessioned2019-03-01T03:44:51Z-
dc.date.available2019-03-01T03:44:51Z-
dc.date.issued2018-
dc.identifier.citationJin, K. [金康]. (2018). Total synthesis of teixobactin and its analogues and a novel desulfurization method for peptide and protein synthesis. (Thesis). University of Hong Kong, Pokfulam, Hong Kong SAR.-
dc.identifier.urihttp://hdl.handle.net/10722/267787-
dc.description.abstractThe problem of multidrug resistance has become increasingly serious due to the abuse of antibiotics. In order to treat infections by these so called “superbugs”, novel antibiotics are urgently needed for the clinic. Toward this end, a new and effective antibiotic, named teixobactin, was discovered in 2015 that showed promise as a new antibacterial lead. Teixobactin exhibits potent antibacterial activity against a series of Gram-positive pathogens, including drug-resistant bacteria such as vancomycin-resistant Enterococcus faecalis and faecium (VRE), methicillin-resistant Staphylococcus aureus (MRSA) and multidrug-resistant Mycobacterium tuberculosis (Mtb). Structurally, teixobactin contains a 13-membered depsipeptide ring consisting of 4 amino acids and a linear exocyclic tail made up of 7 amino acids. To conduct the medicinal chemistry study on teixobactin, we first engaged in the development of its total synthesis. In chapter 2, we adopted a convergent 6+5 strategy and successfully completed the total synthesis of teixobactin with serine ligation as the key step for the convergent synthesis. Meanwhile, a series of teixobactin analogues have been synthesized through the similar convergent method, which has allowed us to establish the structure-activity relationship to search for more promising antibacterial lead compounds. Cysteine-based native chemical ligation (NCL) is a widely used approach for peptide and protein chemical synthesis since its discovery by Kent and co-workers. However, the relative scarity of cysteine residues in naturally occurring proteins limits its widespread use. In chapter 3, we have developed a powerful P-B desulfurization strategy to expand the application of NCL-desulfurization. In addition, we have applied this novel method for the total syntheses of several natural peptides and proteins. -
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.rightsThis work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.-
dc.subject.lcshPeptide antibiotics-
dc.subject.lcshProteins - Synthesis-
dc.titleTotal synthesis of teixobactin and its analogues and a novel desulfurization method for peptide and protein synthesis-
dc.typePG_Thesis-
dc.description.thesisnameDoctor of Philosophy-
dc.description.thesislevelDoctoral-
dc.description.thesisdisciplineChemistry-
dc.description.naturepublished_or_final_version-
dc.date.hkucongregation2019-
dc.identifier.mmsid991044081524403414-

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