Synthesis of an Undecasaccharide Featuring an Oligomannosidic Heptasaccharide and a Bacterial Kdo-lipid A Backbone for Eliciting Neutralizing Antibodies to Mammalian Oligomannose on the HIV-1 Envelope Spike.

Authors:
NIno Trattnig
NIno Trattnig
University of Natural Resources and Life Sciences
Markus Blaukopf
Markus Blaukopf
University of British Columbia
Ralph Pantophlet
Ralph Pantophlet
The Scripps Research Institute
United States
Paul Kosma
Paul Kosma
University of Natural Resources and Applied Life Sciences
Austria

J Am Chem Soc 2019 May 30;141(19):7946-7954. Epub 2019 Apr 30.

Department of Chemistry , University of Natural Resources and Life Sciences , A-1190 Vienna , Austria.

Lipooligosaccharides (LOS) from the bacterium Rhizobium radiobacter Rv3 are structurally related to antigenic mammalian oligomannoses on the HIV-1 envelope glycoprotein spike that are targets for broadly neutralizing antibodies. Here, we prepared a hybrid structure of viral and bacterial epitopes as part of a vaccine design strategy to elicit oligomannose-specific HIV-neutralizing antibodies using glycoconjugates based on the Rv3 LOS structure. Starting from a KdoGlcNAc tetrasaccharide precursor, a central orthogonally protected mannose trichloroacetimidate donor was coupled to OH-5 of the innermost Kdo residue. To assemble larger glycans, the N-acetylamino groups of the glucosamine units were converted to imides to prevent formation of unwanted imidate byproducts. Blockwise coupling of the pentasaccharide acceptor with an α-(1→2)-linked mannotriosyl trichloroacetimidate donor introduced the D1-arm fragment. Glycosylation of O-6 of the central branching mannose with an α-(1→2)-α-(1→6)-linked mannotriosyl trichloroacetimidate donor unit then furnished the undecasaccharide harboring a D3-arm extension. Global deprotection yielded the 3-aminopropyl ligand, which was activated as an isothiocyanate or adipic acid succinimidoyl ester and conjugated to CRM. However, representative oligomannose-specific HIV-neutralizing antibodies bound the undecasaccharide conjugates poorly. Possible reasons for this outcome are discussed herein along with paths for improvement.

Download full-text PDF

Source
http://dx.doi.org/10.1021/jacs.9b02872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524000PMC
May 2019
1 Read

Publication Analysis

Top Keywords

trichloroacetimidate donor
12
neutralizing antibodies
8
oligomannose-specific hiv-neutralizing
8
hiv-1 envelope
8
mannotriosyl trichloroacetimidate
8
hiv-neutralizing antibodies
8
units converted
4
converted imides
4
glucosamine units
4
groups glucosamine
4
n-acetylamino groups
4
imides prevent
4
glycans n-acetylamino
4
formation unwanted
4
coupling pentasaccharide
4
pentasaccharide acceptor
4
acceptor α-1→2-linked
4
blockwise coupling
4
byproducts blockwise
4
larger glycans
4

Altmetric Statistics

Similar Publications