Synthesis of a polymerizable, bivalent glycan mimetic of the HIV envelope spike gp120

Abstract

A synthetic study on the creation of a bivalent, ROMP capable monomer has the ability to be polymerized into the corresponding neo-glycopolymer mimetic of the surface glycans on gp120 envelope spike of the HIV virus. In our approach, we have developed a new strategy for orthogonally attaching both the terminal Manα1-2Man disaccharide unit of the D1 arm of Man9GlcNAc2 of HIV gp120 and the terminal Manα1-2 unit of its D2 arm to a bivalent scaffold to produce the corresponding polymerizable monomer. The Manα1-2 saccharide moieties were assembled using a nickel catalyst, Ni(4-F-PhCN) 4 (OTf) 2 , to activate trihaloacetimidate donors under mild and operationally simple procedure. KeywordsHIV; Glycopolymer; Carbohydrate Synthesis; Nickel Catalyzed Human immunodeficiency virus (HIV) has evolved into one of the most threatening global viruses since its first isolation in 1983. Despite extensive research efforts in more than two decades, the conception of a synthetic HIV vaccine capable of eliciting broadly-neutralizing antibodies, has thus far proven elusive. 1 A principal explanation for this phenomenon focuses on the heavily glycosylated viral envelope, comprised of oligosaccharide fragments, which may disguise the virion from immune responses if they are recognized as "self", 2 the virus also utilizes its "glycan shield" to prevent protein-specific antibodies from binding to the inner protein core. 3 The isolation of carbohydrate-specific broadly-neutralizing antibody 2G12, capable of binding to HIV gp120's surface oligosaccharides, 4,5 suggests that the carbohydrate shield of HIV could be considered as a potential target for neutralization. 6 This elucidation inspired the use of glycan antigens towards the development of potential vaccines. Along with the 2G12 antibody, several other carbohydrate-specific broadly- hien-nguyen@uiowa.edu Phone: 319-384-1887 Fax: 319-335-1270. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Supplementary dataSupplementary data associated with this article can be found in the online version, at http:// Figure 1) of gp120. The crystal structure of 2G12 in particular revealed that approximately 85% of the contact with gp120 was through this terminal disaccharide unit, 6,[8][9] and that its unusual Fab domain-swapped structure provided for additional multivalent binding sites. 6,10 This discovery suggests that a majority of the binding event may be conserved upon utilization of only a fraction of the Man 9 GlcNAc 2 epitope. Our objective is to develop a glycan mimetic of HIV gp120 that potentially binds to glycan-specific bnAbs; this synthe...

Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry

“…Recently, our group synthesized a similar heterobifunctional monomer with the calculated spacing between anomeric centers of mannose units at about 13 Å using solid state 3D-modeling software. 46 Based on this calculation, we hypothesize that the proximity between two sugar units would facilitate enhanced binding to the extended binding site of Con A in a similar manner as observed by Brewer with branched trisaccharides. 47 With this approach in mind, each glycan (Scheme 2) with its respective orthogonal functionality was sequentially coupled to the polymerizable scaffold 21 (Schemes 3 – 5) bearing the terminal alkyne and carboxylic acid functional groups.…”

“…Even though β -glucose itself does not bind to Con A, we hypothesize that the amannose bound to Con A might facilitate interaction of β -glucose with the extended binding site of Con A due to the close proximity (13 Å) of β-glucose to α–mannose residues in the designed polymerizable scaffold. 46 …”

Cu-Catalyzed Click Reaction in Carbohydrate Chemistry

“…Structure of Man9­GlcNAc 2 and the terminal Man-α-(1–2) unit to form a bivalent scaffold with a polymerizable monomer …”

Cu(I)-Catalyzed Click Chemistry in Glycoscience and Their Diverse Applications

“…Nguyen and co-workers synthesized a bivalent polymerizable glycan monomer that could be polymerized under standard reaction conditions in the targeted neoglycopolymer mimetic of the surface glycans of the gp120 envelop of HIV . In order to develop the bivalent polymerizable monomer 449 , ROMP-capable rigid linker 447 exhibiting orthogonal functionality was chosen and was coupled with the terminal monosaccharide amine 446 to give scaffold 448 , followed by CuAAC click with the terminal Man−α-1,2-Man disaccharide unit of the D1 arm of Man9GlcNAc 2 of HIV gp120 using CuI/DIPEA in DMF at 50 °C (Scheme ).…”

“…In order to develop the bivalent polymerizable monomer 449 , ROMP-capable rigid linker 447 exhibiting orthogonal functionality was chosen and was coupled with the terminal monosaccharide amine 446 to give scaffold 448 , followed by CuAAC click with the terminal Man−α-1,2-Man disaccharide unit of the D1 arm of Man9GlcNAc 2 of HIV gp120 using CuI/DIPEA in DMF at 50 °C (Scheme ). The binding affinity of the developed bivalent polymerizable monomer is still under investigation.…”