Cargando…

Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder

Synthetic glycoconjugates are used in the development of vaccines and the design of inhibitors for glycan–protein interactions. The in vivo persistence of synthetic glycoconjugates is an important factor in their efficacy, especially when prolonged interactions with specific cell types may be requir...

Descripción completa

Detalles Bibliográficos
Autores principales: Daskhan, Gour Chand, Motyka, Bruce, Bascom, Roger, Tran, Hanh Thuc, Tao, Kesheng, West, Lori J., Cairo, Christopher W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: RSC 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533409/
https://www.ncbi.nlm.nih.gov/pubmed/36320887
http://dx.doi.org/10.1039/d2cb00126h
_version_ 1784802338643378176
author Daskhan, Gour Chand
Motyka, Bruce
Bascom, Roger
Tran, Hanh Thuc
Tao, Kesheng
West, Lori J.
Cairo, Christopher W.
author_facet Daskhan, Gour Chand
Motyka, Bruce
Bascom, Roger
Tran, Hanh Thuc
Tao, Kesheng
West, Lori J.
Cairo, Christopher W.
author_sort Daskhan, Gour Chand
collection PubMed
description Synthetic glycoconjugates are used in the development of vaccines and the design of inhibitors for glycan–protein interactions. The in vivo persistence of synthetic glycoconjugates is an important factor in their efficacy, especially when prolonged interactions with specific cell types may be required. In this study, we applied a strategy for non-covalent association of an active compound with serum proteins for extension of glycoconjugate half-life in serum. The small molecule, AG10, has previously been used to extend the half-life of small molecules through its high affinity for transthyretin (TTR), a serum protein. Using a tetravalent polyethylene glycol (PEG)-based scaffold we developed a synthetic strategy for glycoconjugates that allowed for controlled addition of multiple tags, such as a TTR affinity tag or fluorophore. We designed a version of AG10 modified at the pyrazole core, named GD10, amenable to our conjugation strategy and introduced to glycoconjugates using a tri-functional linker. This approach allowed for attachment of GD10 and fluorophore tags, as well as carbohydrate antigens. We then tested the influence of the GD10 tag on glycoconjugate half-life in vivo using a mouse model. Our results suggest that the combination of the GD10 tag and the PEG scaffold extended the half-life of glycoconjugates by as much as 10-fold when compared to proteins of similar molecular weight. The GD10 tag was able to extend the half-life of similar glycoconjugates by as much as 2-fold. We observed a role for the terminal saccharide residue of the carbohydrate antigen and confirmed that conjugates were able to penetrate multiple compartments in vivo including bone marrow, lymph nodes, and other organs. The introduction of the GD10 tag did not obstruct the ability of conjugates to interact with lectin receptors. We conclude that serum protein binders can be used to extend the persistence of glycoconjugates in vivo.
format Online
Article
Text
id pubmed-9533409
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher RSC
record_format MEDLINE/PubMed
spelling pubmed-95334092022-10-31 Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder Daskhan, Gour Chand Motyka, Bruce Bascom, Roger Tran, Hanh Thuc Tao, Kesheng West, Lori J. Cairo, Christopher W. RSC Chem Biol Chemistry Synthetic glycoconjugates are used in the development of vaccines and the design of inhibitors for glycan–protein interactions. The in vivo persistence of synthetic glycoconjugates is an important factor in their efficacy, especially when prolonged interactions with specific cell types may be required. In this study, we applied a strategy for non-covalent association of an active compound with serum proteins for extension of glycoconjugate half-life in serum. The small molecule, AG10, has previously been used to extend the half-life of small molecules through its high affinity for transthyretin (TTR), a serum protein. Using a tetravalent polyethylene glycol (PEG)-based scaffold we developed a synthetic strategy for glycoconjugates that allowed for controlled addition of multiple tags, such as a TTR affinity tag or fluorophore. We designed a version of AG10 modified at the pyrazole core, named GD10, amenable to our conjugation strategy and introduced to glycoconjugates using a tri-functional linker. This approach allowed for attachment of GD10 and fluorophore tags, as well as carbohydrate antigens. We then tested the influence of the GD10 tag on glycoconjugate half-life in vivo using a mouse model. Our results suggest that the combination of the GD10 tag and the PEG scaffold extended the half-life of glycoconjugates by as much as 10-fold when compared to proteins of similar molecular weight. The GD10 tag was able to extend the half-life of similar glycoconjugates by as much as 2-fold. We observed a role for the terminal saccharide residue of the carbohydrate antigen and confirmed that conjugates were able to penetrate multiple compartments in vivo including bone marrow, lymph nodes, and other organs. The introduction of the GD10 tag did not obstruct the ability of conjugates to interact with lectin receptors. We conclude that serum protein binders can be used to extend the persistence of glycoconjugates in vivo. RSC 2022-08-23 /pmc/articles/PMC9533409/ /pubmed/36320887 http://dx.doi.org/10.1039/d2cb00126h Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Daskhan, Gour Chand
Motyka, Bruce
Bascom, Roger
Tran, Hanh Thuc
Tao, Kesheng
West, Lori J.
Cairo, Christopher W.
Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title_full Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title_fullStr Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title_full_unstemmed Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title_short Extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
title_sort extending the in vivo persistence of synthetic glycoconjugates using a serum-protein binder
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9533409/
https://www.ncbi.nlm.nih.gov/pubmed/36320887
http://dx.doi.org/10.1039/d2cb00126h
work_keys_str_mv AT daskhangourchand extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT motykabruce extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT bascomroger extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT tranhanhthuc extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT taokesheng extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT westlorij extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder
AT cairochristopherw extendingtheinvivopersistenceofsyntheticglycoconjugatesusingaserumproteinbinder