Chemical, Enzymatic and Chemo-enzymatic Synthesis of Complex Oligosaccharides as Probes of Glycan Functions

• Author / Creator

  Zhang, Junfeng

• Carbohydrates, an essential class of biomolecules, mediate a variety of biological processes. Recent advances in chemical, enzymatic and chemo-enzymatic synthesis have facilitated access to an increasing number of structurally well-defined oligosaccharides. These molecules are serving as invaluable probes for deciphering the biological functions of these glycans and understanding the molecular mechanism underlying their functions, as well as exploring their potential for medicinal use. This thesis is focused on the synthesis of oligosaccharides related to three projects using different synthetic strategies, purely chemical, purely enzymatic and chemo-enzymatic. In the first example, lacto-N-fucopentaose III (LNFPIII), a previously reported immunomodulatory glycan was synthesized via a concise chemical approach, which features two highly regio- and stereoselective glycosylations for the construction of the pentasaccharide, a Birch reduction for deprotection of benzyl ethers, and a thiol–ene coupling for modification of the aglycon. Preliminary biological studies confirmed the potential of LNFPIII to be used as a tolerance-inducing agent in ABO-incompatible (ABOi) heart transplants. In a second example, as part of ABOi heart transplant program, we are interested in creating an ABO-glycan microarray for accurate detection of anti-donor antibody responses in patients undergoing an ABOi transplant. To better mimic natural glycan structures and reveal the effect of structural complexity on antibody–antigen recognition, a panel of poly-LacNAc extended biantennary N- and O-linked glycans capped with blood group A or B antigens were synthesized via an enzymatic approach. These glycans will be used in a glycan microarray to screen serum samples from ABOi heart transplant patients. In the final example, a chemo-enzymatic approach was developed to prepare a library of structurally defined group B Streptococcus type III (GBSIII) oligosaccharides differing in size from 10 up to 50 residues. The route developed involves chemical synthesis of the oligosaccharide backbone and introduction of the side chain by glycosyltransferases. These compounds will be used as probes to gain deeper insight into the role of carbohydrates in activation of the immune system.

• Subjects / Keywords

  • Oligosaccharide
  • Glycoconjugate vaccine
  • Carbohydrates
  • Enzymatic and chemo-enzymatic synthesis

• Graduation date

  Spring 2016

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/R3QB9VM4K

• License

  This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.