Identification of allosteric peptide agonists of CXCR4

Aristidis Sachpatzidis, Benjamin K. Benton, John P. Manfredi, Hua Wang, Andrew Hamilton, Henrik G. Dohlman, Elias Lolis

Research output: Contribution to journalArticle

Abstract

The chemokine receptor CXCR4 is a co-receptor for T-tropic strains of HIV-1. A number of small molecule antagonists of CXCR4 are in development but all are likely to lead to adverse effects due to the physiological function of CXCR4. To prevent these complications, allosteric agonists may be therapeutically useful as adjuvant therapy in combination with small molecule antagonists. A synthetic cDNA library coding for 160,000 different SDF-based peptides was screened for CXCR4 agonist activity in a yeast strain expressing a functional receptor. Peptides that activated CXCR4 in an autocrine manner induced colony formation. Two peptides, designated RSVM and ASLW, were identified as novel agonists that are insensitive to the CXCR4 antagonist AMD3100. In chemotaxis assays using the acute lymphoblastic leukemia cell line CCRF-CEM, RSVM behaves as a partial agonist and ASLW as a superagonist. The superagonist activity of ASLW may be related to its inability to induce receptor internalization. In CCRF-CEM cells, the two peptides are also not inhibited by another CXCR4 antagonist, T140, or the neutralizing monoclonal antibodies 12G5 and 44717.111. These results suggest that alternative agonist-binding sites are present on CXCR4 that could be screened to develop molecules for therapeutic use.

Original languageEnglish (US)
Pages (from-to)896-907
Number of pages12
JournalJournal of Biological Chemistry
Volume278
Issue number2
DOIs
StatePublished - Jan 10 2003

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Peptides
Molecules
Tropics
Chemokine Receptors
Therapeutic Uses
Chemotaxis
Neutralizing Antibodies
Gene Library
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Yeast
HIV-1
Assays
Yeasts
Binding Sites
Monoclonal Antibodies
Cells
Cell Line
Therapeutics
JM 3100
T140 peptide

ASJC Scopus subject areas

  • Biochemistry

Cite this

Sachpatzidis, A., Benton, B. K., Manfredi, J. P., Wang, H., Hamilton, A., Dohlman, H. G., & Lolis, E. (2003). Identification of allosteric peptide agonists of CXCR4. Journal of Biological Chemistry, 278(2), 896-907. https://doi.org/10.1074/jbc.M204667200

Identification of allosteric peptide agonists of CXCR4. / Sachpatzidis, Aristidis; Benton, Benjamin K.; Manfredi, John P.; Wang, Hua; Hamilton, Andrew; Dohlman, Henrik G.; Lolis, Elias.

In: Journal of Biological Chemistry, Vol. 278, No. 2, 10.01.2003, p. 896-907.

Research output: Contribution to journalArticle

Sachpatzidis, A, Benton, BK, Manfredi, JP, Wang, H, Hamilton, A, Dohlman, HG & Lolis, E 2003, 'Identification of allosteric peptide agonists of CXCR4', Journal of Biological Chemistry, vol. 278, no. 2, pp. 896-907. https://doi.org/10.1074/jbc.M204667200
Sachpatzidis A, Benton BK, Manfredi JP, Wang H, Hamilton A, Dohlman HG et al. Identification of allosteric peptide agonists of CXCR4. Journal of Biological Chemistry. 2003 Jan 10;278(2):896-907. https://doi.org/10.1074/jbc.M204667200
Sachpatzidis, Aristidis ; Benton, Benjamin K. ; Manfredi, John P. ; Wang, Hua ; Hamilton, Andrew ; Dohlman, Henrik G. ; Lolis, Elias. / Identification of allosteric peptide agonists of CXCR4. In: Journal of Biological Chemistry. 2003 ; Vol. 278, No. 2. pp. 896-907.
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