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- Johansson, Susanne, 1977-
(författare)
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Design and Synthesis of Sialic Acid Conjugates as Inhibitors of EKC-causing Adenoviruses
- 2008
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The combat against viral diseases has been, and still is, a major challenge in the field of drug development. Viruses are intracellular parasites that use the host cell ma-chinery for their replication and release. Therefore it is difficult to target and destroy the viral particle without disturbing the essential functions of the host cell. This thesis describes studies towards antiviral agents targeting adenovirus type 37 (Ad37), which causes the severe ocular infection epidemic keratoconjunctivitis (EKC). Cell surface oligosaccharides serve as cellular receptors for many pathogens, including viruses and bacteria. For EKC-causing adenoviruses, cell surface oligo-saccharides with terminal sialic acid have recently been shown to be critical for their attachment to and infection of host cells. The work in this thesis support these re-sults and identifies the minimal binding epitope for viral recognition. As carbo-hydrate–protein interactions in general, the sialic acid–Ad37 interaction is very weak. Nature overcomes this problem and vastly improves the binding affinity by presenting the carbohydrates in a multivalent fashion. Adenoviruses interact with their cellular receptors via multiple fiber proteins, whereby it is likely that the ideal inhibitor of adenoviral infections should be multivalent. This thesis includes design and synthesis of multivalent sialic acid glycoconjugates that mimic the structure of the cellular receptor in order to inhibit adenoviral attachment to and infection of human corneal epithelial (HCE) cells. Synthetic routes to three different classes of sialic acid conjugates, i.e. derivatives of sialic acid, 3’-sialyllactose and N-acyl modified sialic acids, and their multivalent counterparts on human serum albumine (HSA) have been developed. Evaluation of these conjugates in cell binding and cell infectivity assays revealed that they are effective as inhibitors. Moreover the results verify the hypothesis of the multivalency effect and clearly shows that the power of inhibition is significantly increased with higher orders of valency. Potential inhibi-tors could easily be transferred to the eye using a salve or eye drops, and thereby they would escape the metabolic processes of the body, a major drawback of using carbohydrates as drugs. The results herein could therefore be useful in efforts to develop an antiviral drug for treatment of EKC.
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| 3. |
- Rydner, Lina, 1978-
(författare)
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Development of strategies for construction of thioglycoside building blocks corresponding to repeating triads of Cryptococcus neoformans GXM capsular polysaccharide
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on the development of methods for synthesis of thioglycoside building blocks corresponding to the repeating units of the capsular polysaccharide (CPS) of Cryptococcus neoformans, an opportunistic fungal pathogen. The building blocks are suitable for construction of large synthetic oligosaccharides related to the native CPS-structures which are to be used in biological studies in order to identify protective epitopes with the aim to develop a glycoconjugate vaccine against C. neoformans infections. Chapter 3 describes the improved synthesis of di- and trisaccharide glucuronic acid-containing thioglycoside blocks by introduction of the carboxylic acid motif at the di- and trisaccharide level through oxidation of a glucose residue. The new approach requires a number of extra steps, but has proven to be more reliable and more easily reproducible since problems encountered in glycosylations with glucuronic acid donors and benzylation of glucuronic acid-containing derivatives are circumvented. In Chapter 4 the development of a synthetic route to xylose-substituted tri- and tetrasaccharide building blocks where the protecting group strategy allows for orthogonal glycosylations with thioglycoside acceptors is discussed. Chapter 5 describes the synthetic pathway to the glucuronic acid-containing derivatives according to the methodology developed in Chapter 4 and the assembly of a hexasaccharide building block corresponding to the repeating triad of serotype A. In Appendix І an alternative strategy for synthesis of glucuronic acid-substituted derivatives by direct introduction of a perbenzylated glucuronic acid trichloroacetimidate donor where stereoselectivity is achieved through the use of an 1,6-anhydro acceptor.
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- Slättegård, Rikard, 1979-
(författare)
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Synthesis of Structures Related to the Capsular Polysaccharide of Neisseria meningitidis Serogroup A and to Mycothiol
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the synthesis of structures related to the capsular polysaccharide of Neisseria meningitidis serogroup A and the synthesis of analogues of mycothiol, a compound produced by Mycobacterium tuberculosis. The first part of the thesis describes the synthesis of structural elements present in the native capsular polysaccharide of Neisseria meningitidis serogroup A. In this part, an improved synthesis of 2-azido-2-deoxy-D-mannopyranose is included. The second part of the thesis describes the formation of stable C-phosphonate analogues related to the capsular polysaccharide. The last part outlines the formation of analogues of mycothiol, where the syntheses of a bicyclic analogue and a thioglycosidic analogue are described.
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- Mannerstedt, Karin, 1975-
(författare)
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Synthesis of Oligosaccharides from the Inner Core Structure of Haemophilus Influenzae and Neisseria meningitidis Lipopolysaccharides
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis describes the synthesis of oligosaccharides corresponding to different parts of the lipopolysaccharide (LPS) inner core structure from Haemophilus influenzae and Neisseria meningitidis. Chapter 2 describes the synthesis of a protected trisaccharide common to H. influenzae and N. meningitidis LPS, which can be used as a versatile precursor in further syntheses of larger LPS structures. In Chapter 3 syntheses towards phosphoethanolamine substituted trisaccharides corresponding to H. influenzae and N. meningitidis structures are presented. In Chapter 4 the synthesis of a H. influenzae tetrasaccharide structure, with and without a phosphoethanolamine substituent in the 6-position of the second heptose unit, is described. Conjugation to biotin of these two tetrasaccharides is also performed. Chapter 5 describes the synthesis of a spacer-equipped Kdo acceptor that is subsequently attached to the tetrasaccharide described in Chapter 4 forming a pentasaccharide from the inner core structure of H. influenzae. Similar to the synthesis of the tetrasaccharide, a phosphoethanolamine is attached to the 6 position of the second heptose. Chapter 5 also describes the synthesis of various Kdo thioglycoside donors and their evaluation in glycosylation reactions using different promoters and reaction conditions.
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