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Synthesis of a C-glycoside analogue of beta-D-galactosyl hydroxynorvaline and its use in immunological studies

Wellner, E ; Gustafsson, T ; Bäcklund, Johan LU ; Holmdahl, Rikard LU and Kihlberg, J (2000) In ChemBioChem 1(4). p.272-280
Abstract
A C-linked isostere of beta-D-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256--270) from typeII collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using... (More)
A C-linked isostere of beta-D-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256--270) from typeII collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by classII MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked beta-D-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256--270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of beta-D-Gal-Hyl(264) in CII(256--270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis. (Less)
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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
ChemBioChem
volume
1
issue
4
pages
272 - 280
publisher
John Wiley & Sons Inc.
external identifiers
  • pmid:11828419
  • scopus:0039174266
ISSN
1439-4227
DOI
10.1002/1439-7633(20001117)1:4<272::AID-CBIC272>3.0.CO;2-W
language
English
LU publication?
yes
additional info
The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Inflammation Research (013212019)
id
060ccde5-6bb2-45ea-8cb8-808005922525 (old id 1116568)
date added to LUP
2016-04-01 12:33:40
date last changed
2022-02-26 08:44:07
@article{060ccde5-6bb2-45ea-8cb8-808005922525,
  abstract     = {{A C-linked isostere of beta-D-galactosylated hydroxynorvaline has been prepared in eight steps from per-O-benzylated galactopyranolactone. Addition of a homoallylic Grignard reagent to the lactone, reduction of the resulting hemiacetal with triethylsilane, and a Wittig reaction with Garner's aldehyde were key steps in this synthesis. The C-linked building block was then incorporated at position 264 into the fragment CII(256--270) from typeII collagen by solid-phase synthesis using a combination of the tert-butoxycarbonyl (Boc) and 9-fluorenylmethoxycarbonyl (Fmoc) protective group strategies. Deprotection of the benzylated C-linked galactosyl moiety was achieved simultaneously with cleavage of the glycopeptide from the solid phase by using triethylsilyl trifluoromethanesulfonate in TFA. Helper T-cell hybridomas obtained in a mouse model for rheumatoid arthritis responded to the C-linked glycopeptide when presented by classII MHC molecules. However, 10- to 20-fold higher concentrations were required as compared to when O-linked beta-D-galactosylated hydroxynorvaline or hydroxylysine (Hyl) were present at position 264 of CII(256--270). Thus, replacement of a single oxygen atom by a methylene group in the carbohydrate moiety of a glycopeptide antigen had a substantial influence on the T-cell response. This reveals that T cells are able to recognize the carbohydrate moiety of glycopeptide antigens with high specificity. Finally, the results suggest that structural modifications of beta-D-Gal-Hyl(264) in CII(256--270) may give altered peptide ligands that can be used for induction of tolerance in autoimmune rheumatoid arthritis.}},
  author       = {{Wellner, E and Gustafsson, T and Bäcklund, Johan and Holmdahl, Rikard and Kihlberg, J}},
  issn         = {{1439-4227}},
  language     = {{eng}},
  number       = {{4}},
  pages        = {{272--280}},
  publisher    = {{John Wiley & Sons Inc.}},
  series       = {{ChemBioChem}},
  title        = {{Synthesis of a C-glycoside analogue of beta-D-galactosyl hydroxynorvaline and its use in immunological studies}},
  url          = {{http://dx.doi.org/10.1002/1439-7633(20001117)1:4<272::AID-CBIC272>3.0.CO;2-W}},
  doi          = {{10.1002/1439-7633(20001117)1:4<272::AID-CBIC272>3.0.CO;2-W}},
  volume       = {{1}},
  year         = {{2000}},
}