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Amino Acids

, Volume 43, Issue 1, pp 219–232 | Cite as

Cyclic RGD peptides interfere with binding of the Helicobacter pylori protein CagL to integrins αVβ3 and α5β1

  • Jens Conradi
  • Sylwia Huber
  • Katharina Gaus
  • Felix Mertink
  • Soledad Royo Gracia
  • Ulf Strijowski
  • Steffen Backert
  • Norbert SewaldEmail author
Original Article

Abstract

The human pathogen Helicobacter pylori that may cause different gastric diseases exploits integrins for infection of gastric cells. The H. pylori protein CagL present on the outer region of the type IV secretion pilus contains an RGD sequence (-Arg-Gly-Asp-) that enables binding to cells presenting integrins α5β1 and αVβ3. This interaction can be inhibited with conformationally designed cyclic RGD peptides derived from the CagL epitope -Ala-Leu-Arg-Gly-Asp-Leu-Ala-. The inhibition of the CagL–αVβ3 interaction by different RGD peptides strongly suggests the importance of the RGD motif for CagL binding. CagL point mutants (RAD, RGA) show decreased affinity to integrin αVβ3. Furthermore, structure–activity relationship studies with cyclic RGD peptides in a spatial screening approach show the distinct influence of the three-dimensional arrangement of RGD motif on the ability to interfere with this interaction. Resulting from these studies, similar structural requirements for the CagL epitope as previously suggested for other ligands of integrin αVβ3 are proposed.

Keywords

CagL Integrins αVβ3 RGD peptides SAR studies 

Abbreviations

D-PBS

Dulbecco's phosphate buffered saline

DIPEA

Diisopropylethylamine

DMF

Dimethylformamide

EDTA

Ethylenediaminetetraacetic acid

HATU

1-[Bis-(dimethylamino)methyliumyl]-1H-1,2,3-triazolo[4,5-b]pyridine-3-oxide hexafluorophosphate

MEM

Minimum essential medium

MES

2-(N-Morpholino)ethanesulfonic acid

NMP

1-Methyl-2-pyrrolidone

Pbf

2,2,4,6,7-Pentamethyldihydrobenzofuran-5-ylsulfonyl

TBTU

3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide tetrafluoroborate

TFA

Trifluoroacetic acid

TIS

Triisopropylsilane

Notes

Acknowledgments

The authors thank Carmela Michalek and Marco Wißbrock for skillful technical assistance. Financial support came from the NRW Graduate School in Bioinformatics and Genome Research, Bielefeld University (PhD Fellowship to K.G.), the EU (Marie Curie Fellowship to S.R.G.), and Deutsche Forschungsgemeinschaft, which is gratefully acknowledged.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

726_2011_1066_MOESM1_ESM.doc (766 kb)
Supplementary material 1 (DOC 766 kb)

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Jens Conradi
    • 1
  • Sylwia Huber
    • 1
    • 4
  • Katharina Gaus
    • 1
    • 3
  • Felix Mertink
    • 1
  • Soledad Royo Gracia
    • 1
    • 6
  • Ulf Strijowski
    • 1
    • 5
  • Steffen Backert
    • 2
  • Norbert Sewald
    • 1
    Email author
  1. 1.Department of ChemistryBielefeld UniversityBielefeldGermany
  2. 2.School of Biomolecular and Biomedical SciencesUniversity College DublinDublinIreland
  3. 3.SyngentaSteinSwitzerland
  4. 4.F. Hoffmann-La RocheBaselSwitzerland
  5. 5.German Institute of Food TechnologiesQuakenbrückGermany
  6. 6.Institute for Research in BiomedicineBarcelonaSpain

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