Synthesis of heparan sulfate oligosaccharides to study heavy metals binding and adjuvant activity

Abstract

Heparan sulfate (HS) is a complex polysaccharide that is ubiquitous on all mammalian cell surfaces and extracellular matrices. The complexity of HS is encoded by broad sulfation patterns and uronic acid compositions. This pronounced structural heterogeneity of HS facilitates a wide range of biological activities. In the last two decades, carbohydrate chemists intensively pursued the synthesis of well-defined HS oligosaccharides to understand the structural-activity relationships (SARs). These studies revealed that sulfation codes and uronic acid variants synergistically modulate HS-protein interactions (HSPI). Furthermore, a growing number of studies associating the conformation plasticity of L-Iduronic acid, an uronic acid composition, provide a rationale to fine-tune the microenvironment to modulate the HSPI. In addition to traditional growth factors and chemokines binding, several non-canonical roles of HS are also reported, including HS binding to cell-penetrating peptides and metal ions. This thesis presents the synthesis of well-defined HS oligosaccharides and deciphers their binding affinity to heavy metal ions and toll-like receptors (TLRs). The thesis is divided into total of five chapters, and the summary of each chapter is outlined below. In Chapter 1, a brief introduction is given about the cell surface glycans and discussed the structural heterogeneity of heparan sulfate, its biosynthesis and the current insight into the structure-activity relationship (SARs) of specific uronic acid-composed HS with growth factors, chemokines and anticoagulants proteins. Chapter 2 describes an efficient total synthesis of HS tetrasaccharide composed of glucuronic acid. The key features of synthesis include the divergent strategy to obtain 3-O sulfated and 6-O-sulfate HS tetrasccharides and evaluated their binding with heavy metal ions, such as lead(II), cadmium(II) and mercury(II), which are a common toxic pollutant. Here, we immobilized HS tetrasaccharides on electrodes using electrografting technique and exposed