Skip to main content
SpringerLink
Log in

Uncharged P-selectin blockers

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

The blocking potency of P- and L-selectin was studied for certain small molecule mannosides and their polyacrylamide (PAA, 30 kDa) conjugates in comparison to SiaLex and fucoidan. Two experimental systems were used: (1) solid phase static assay based on recombinant selectins, and (2) P-selectin dependent rat peritoneal inflammation. βMan-SC6H4NO2-p was four times more potent P-selectin inhibitor as compared to SiaLex. Docking of this molecule onto the P-selectin carbohydrate-binding site demonstrated that a nitro group enabled an electrostatic interaction with residue Lys 84, while the phenyl ring and the CH2 at C-6 contacted the CH2 groups of the same Lys residue. In vivo, βMan-SC6H4NO2-p blocked experimental inflammation better than SiaLex, but significantly lower than fucoidan. In vitro Man-polyacrylic acid conjugates appeared to be very potent inhibitors comparable to fucoidan, uncharged Man-PAA proved rather active, comparable to SiaLex-PAA both in vitro, and in vivo, whereas mannan did not display any P-selectin blocking effect. Published in 2004.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Vestweber D, Blanks JE, Mechanisms that regulate the function of the selectins and their ligands, Physiol Rev 79, 181-213 (1999).

    PubMed  CAS  Google Scholar 

  2. Simanek EE, McGarvey GJ, Jablonowski JA, Wong C-H, Selectincarbohydrate interactions: from natural ligands to designed mimics, Chem Rev 98, 833-62 (1998).

    Article  PubMed  CAS  Google Scholar 

  3. McEver RP, Moore KL, Cummings, RD, P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin, J Biol Chem 270, 11025-8 (1995).

    Article  PubMed  CAS  Google Scholar 

  4. Torgersen D, Mullin NP, Drickamer K, Mechanism of ligand binding to E-and P-selectin analyzed using selectin/mannose-binding protein chimeras. J Biol Chem 273, 6254-61 (1998).

    Article  PubMed  CAS  Google Scholar 

  5. Kogan TP, Dupre B, Keller KM, Scott IL, Bui H, Market RV, Beck PJ, Voytus JA, Revelle BM, Scott D, Rational design and synthesis of small molecule, non-oligosaccharide selectin inhibitors: (alpha-D-mannopyranosyloxy) biphenyl-substituted carboxylic acids, J Med Chem 38, 4976-84 (1995).

    PubMed  CAS  Google Scholar 

  6. Somers WS, Tang J, Shaw GD, Camphausen RT, Insights into the molecular basis of leukocyte tethering and rolling revealed by structures of P-and E-selectin bound to SLex and PSGL-1, Cell 103, 467-79 (2000).

    Article  PubMed  CAS  Google Scholar 

  7. Pochechueva TV, Galanina OE, Bird MI, Nifantiev NE, Bovin NV, Assembly of P-selectin ligands on a polymeric template, Chem Biol 9, 757-62 (2002).

    Article  PubMed  CAS  Google Scholar 

  8. Zemlyanukhina TV, Nifant'ev NE, Shashkov AS, Tsvetkov YE, Bovin NV, Selectin receptors: synthesis of spacer-armed sulfated trisaccharides Lewis A and Lewis X and neoglycoconjugates thereof, Carbohydrate Lett 1, 277-84 (1995).

    CAS  Google Scholar 

  9. Nifant'ev NE, Tsvetkov YE, Shashkov AS, Kononov LO, Menshov VM, Tuzikov AB, Bovin NV, Selectin receptors 4: synthesis of tetrasaccharides sialyl Lewis A and sialyl Lewis X containing a spacer group, J Carbohydr Chem 15, 939-53 (1996).

    Google Scholar 

  10. Bovin NV, Korchagina EYu, Zemlyanukhina TV, Byramova NE, Galanina OE, Zemlyakov AE, Ivanov AE, Zubov VP, Mochalova LV, Synthesis of polymeric neoglycoconjugates based on Nsubstituted polyacrylamide, Glycoconj J 10, 142-51 (1993).

    Article  PubMed  CAS  Google Scholar 

  11. Gordeeva EA, Tuzikov AB, Galanina OE, Pochechueva TV, Bovin NV, Microscale synthesis of glycoconjugate series and libraries, Anal Biochem 278, 230-2 (2000).

    Article  PubMed  CAS  Google Scholar 

  12. Priest R, Nawaz S, Green PM, Bird MI, Adhesion of eosinophils to E-& P-selectin, Biochem Soc Trans 23, 162S (1995).

    PubMed  CAS  Google Scholar 

  13. Game SM, Rajapurohit PK, Clifford M, Bird MI, Priest R, Bovin NV, Nifant'ev NE, O'Beirne G, Cook ND, Scintillation proximity assay for E-, P-, and L-selectin utilizing polyacrylamide-based neoglycoconjugates as ligands, Anal Biochem 258, 127-35 (1998).

    Article  PubMed  CAS  Google Scholar 

  14. Preobrazhenskaya ME, Berman AE, Mikhailov VI, Ushakova NA, Mazurov AV, Semenov AV, Usov AI, Nifant'ev NE, Bovin NV, Fucoidan inhibits leukocyte recruitment in a model peritoneal inflammation in rat and blocks interaction of P-selectin with its carbohydrate ligand, Biochem Mol Biol Int 43, 443-51 (1997).

    PubMed  CAS  Google Scholar 

  15. Mulligan MS, Paulson JC, De Frees S, Zheng ZL, Lowe JB, Ward PA, Protective effects of oligosaccharides in P-selectin-dependent lung injury, Nature 364, 149-51 (1993).

    Article  PubMed  CAS  Google Scholar 

  16. Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE, The Protein Data Bank, Nucleic Acids Res 28, 235-42 (2000).

    Article  PubMed  CAS  Google Scholar 

  17. Clark M, Cramer RD I, van den Opdenbosch N, Validation of the general purpose Tripos 5.2 force field, J Comput Chem 10, 982-1012 (1989).

    Article  CAS  Google Scholar 

  18. Imberty A, Bettler E, Karababa M, Mazeau K, Petrova P, Pérez S, Building sugars: The sweet part of structural biology. In Perspectives in Structural Biology, edited by Vijayan M, Yathindra N, Kolaskar AS (plHyderabad: Indian Academy of Sciences and Universities Press,1999), pp. 392-409

  19. Le Questel JY, Mouhous-Rious N, Pérez S, The crystal and molecular structures of 4-cyanophenyl 1,5-dithio-?-D-Xylopyranoside S-5 oxide and 4-Ethyl-2-oxo-2H-1-benzopyran-7-yl, 5-thio-?-D-xylopyranoside S-5 oxide, Carbohydr Res 302, 53-66 (1997).

    Article  CAS  Google Scholar 

  20. Waldherr-Teschner M, Goetze T, Heiden W, Knoblauch M, Vollhardt H, Brickmann J, MOLCAD–Computer aided visualization and manipulation of models in molecular science. InAdvances in Scientific Visualization, edited by Post FH, Hin AJS (Heidelberg: Springer, 1992), pp. 58-67.

    Google Scholar 

  21. Stoolman LM, Rosen SD, Possible role for cell-surface carbohydrate-binding molecules in lymphocyte recirculation, J Cell Biol 96, 722-9 (1983).

    Article  PubMed  CAS  Google Scholar 

  22. Ng KK, Drickamer K, Weis WI, Structural analysis of monosaccharide recognition by rat liver mannose-binding protein, J Biol Chem 271, 663-74 (1996).

    Article  PubMed  CAS  Google Scholar 

  23. Weis WI, Drickamer K, Hendrickson WA, Structure of a C-type mannose-binding protein complexed with an oligosaccharide, Nature 360, 127-34 (1992).

    Article  PubMed  CAS  Google Scholar 

  24. Hollenbaugh D, Bajorath J, Stenkamp R, Aruffo A, Interaction of P-selectin (CD62) and its cellular ligand: analysis of critical residues, Biochemistry 32, 2960-6 (1993).

    Article  PubMed  CAS  Google Scholar 

  25. Ushakova NA, Preobrazhenskaya ME, Nifant'ev NE, Vozney YaV, Pochechueva TV, Bovin NV, Effect of mannose derivatives on rat and mouse selectin-dependent inflammation, Vopr Med Khim 47, 491-7 (2001).

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Shemyakin Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    T.V. Pochechueva, O.E. Galanina, M.A. Sablina & N.V. Bovin

  2. Orehovich Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow, Russia

    N.A. Ushakova & M.E. Preobrazhenskaya

  3. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia

    N.E. Nifantiev, Yu.V. Tsvetkov & Ya.V. Vozney

  4. CERMAV-CNRS (affiliated with Université Joseph Fourier), BP 53, F-38041, Grenoble cedex 09, France

    A. Imberty

Authors
  1. T.V. Pochechueva
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O.E. Galanina
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N.A. Ushakova
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M.E. Preobrazhenskaya
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M.A. Sablina
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. N.E. Nifantiev
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu.V. Tsvetkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ya.V. Vozney
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. A. Imberty
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. N.V. Bovin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to N.V. Bovin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pochechueva, T., Galanina, O., Ushakova, N. et al. Uncharged P-selectin blockers. Glycoconj J 20, 91–97 (2003). https://doi.org/10.1023/B:GLYC.0000018583.63140.91

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/B:GLYC.0000018583.63140.91

Search

Navigation