GLYCAN THERAPEUTICS CORPORATION — Department of Health and Human Services SBIR Phase II: NCI

Description

The goal of this contract is to synthesize a heparan sulfate HS library consisting of structurally homogeneous oligosaccharides in response to an SBIR contract call from NCl Chemically Defined Glycan Libraries The Contractor specializes in the synthesis of structurally diverse HS oligosaccharides The Contractor has built an innovative chemoenzymatic method for Glycan synthesis Polymeric HS contains the disaccharide repeating units of glucuronic or iduronic acid linked to glucosamine that carry sulfo groups Chemical synthesis of structurally homogeneous HS oligosaccharides is extremely difficult The chemoenzymatic method reduces synthetic complexity providing a cost effective approach to prepare a diverse collection of HS oligosaccharides A library of oligosaccharides with different sizes and sulfation patterns shall be constructed using this method The library represents the basic structural elements found in naturally occurring HS Synthesis shall be carried out under good laboratory practice GLP at a scale of mg for each compound which amount is sufficient for structural analysis by NMR and mass spectrometry as well as the purity analysis by anion exchange high performance liquid chromatography HPLC Four milestones for sample preparations and deliveries are clearly marked Heparan sulfate HS is a member of glycosaminoglycan familythat is present in large quantities on the cell surface and in the extracellular matrix HS is a highly sulfated polysaccharide with a disaccharide repeating unit of glucuronic acid GLcA or iduronic acid ldoA linked to glucosamine Both ldoA and glucosamine residues carry sulfo groups HS participates in numerous biological processes including embryonic development assisting viral and bacterial infections and regulating blood coagulation The sulfation patternsand the location of ldoA residues as well as the size of HS molecules play critical roles in determining the functions HS Unfortunately knowledge of HS is far less developed than knowledge of proteins and nucleic acids One grand challenge in HS studies is to make HS oligosaccharides widely available to the scientific research community Chemical synthesis of HS has been taken to respond to this challenge However the facts that complicated synthesisand low yield of products led to the unsuitableness for oligosaccharide library construction and for HS market The objective of this contract is to employ a state of the art chemoenzymatic approach to synthesize HS oligosaccharides with different structures under GLP conditions A total of oligosaccharides in the library have been selected based on the natural structures of HS and shall be synthesized The oligosaccharides cover the range of tetra to nona saccharides consisting of N and sulfation as well as ldoA residues None of these compounds in the library is currently commercially available Each compound has an aldehyde moiety at its reducing end and has a unique chromophoric group for easy detection The purity of each compound is more than The structures of the newly synthesized compounds shall be proven by NMR and Mass spectrometry analyses All oligosaccharides at ug of each compounds along with their NMR spectra shall be delivered to NIH by the end of Phase II The targeted oligosaccharides can be divided into six groups structurally differing in the size sulfation patterns and with or without ldoA residues Each compound has a pAHP para azido hexanamido phenyl capped GlcA end which exhibits similar chemical reactivity to that of the reducing end of a given sugar residue