Synthesis of the repeating disaccharide unit of the tridecasaccharide N-glycan present in HIV gp41

Abstract

Glycosylation is often described as the process by which carbohydrates molecules are covalently attached to a target macromolecule, typically proteins or lipids. This process is considered as one of the most ubiquitous, heterogeneous, non-templated and stereo-chemically complex post translational modification and has many important structural and biophysical roles. Installation of glycans via glycosylation reaction on different bio-macromolecules have huge impact on various biological processes such as fertilization, viral replication, parasitic infection, cell growth, cell-cell adhesion, inflammation and so on.(27) For a better and thorough understanding of the roles of glycans and expanding its scope towards biomedical research, pure glycans with well determined structure are much needed essential tool. Unlike nucleic acids and proteins, which are easily attained in a homogeneous form by using polymerase chain reaction, purification and recombinant technologies, glycans presents in biological system are heterogeneous. Hence, it is often a daunting and cumbersome task to isolate pure glycans from natural system in good quantity. In this context, chemical syntheses of oligosaccharides have become relevant by which homologous glycans can be obtained in larger quantity. In this project I have aimed to synthesize a tridecasachharide N-glycan present in the glycoprotein gp41 of HIV via using the salient features of ethynyl cyclohexyl carbonate glycosyl donor and [Au]-[Ag] catalysis.(1) First full structure of this particular N-glycan was elucidated back in 2016.(20) This highly branched complex glycan is a 13-mer oligosaccharide which is comprised of Galactose, Glucosamine, Mannose and Fucose monosaccharide units. There are ten 1,2-trans linkages and two highly synthetically challenging 1,2-cis linkages present in the oligosaccharide.Human immunodeficiency virus (HIV) houses glycans on the envelope glycoprotein (Env), which play an important role in viral infection and evasion of neutralisation by antibodies.(31) Achieving α-selectivity in fucose and β-selectivity in mannose using this novel glycosyl donor as well as convergent synthesis of the whole glycan are envisioned.