A novel peptide antagonist of CXCR4 derived from the N-terminus of viral chemokine vMIP-II

Biochemistry. 2000 Apr 4;39(13):3782-7. doi: 10.1021/bi992750v.


The viral macrophage inflammatory protein-II (vMIP-II) encoded by Kaposi's sarcoma-associated herpesvirus is unique among all known chemokines in that vMIP-II shows a broad-spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cell entry of human immunodeficiency virus type 1 (HIV-1). To elucidate the mechanism of the promiscuous receptor interaction of vMIP-II, synthetic peptides derived from the N-terminus of vMIP-II were studied. In contrast to the full-length protein that recognizes both CXCR4 and CCR5, a peptide corresponding to residues 1-21 of vMIP-II (LGASWHRPDKCCLGYQKRPLP) was shown to strongly bind CXCR4, but not CCR5. The IC(50) of this peptide in competing with CXCR4 binding of (125)I-SDF-1alpha is 190 nM as compared to the IC(50) of 14.8 nM of native vMIP-II in the same assay. The peptide selectively prevented CXCR4 signal transduction and coreceptor function in mediating the entry of T- and dual-tropic HIV-1 isolates, but not those of CCR5. Further analysis of truncated peptide analogues revealed the importance of the first five residues for the activity with CXCR4. These results suggest that the N-terminus of vMIP-II is essential for its function via CXCR4. In addition, they reveal a possible mechanism for the distinctive interactions of vMIP-II with different chemokine receptors, a notion that may be further exploited to dissect the structural basis of its promiscuous biological function. Finally, the potent CXCR4 peptide antagonist shown here could serve as a lead for the development of new therapeutic agents for HIV infection and other immune system diseases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Anti-HIV Agents / chemistry*
  • Anti-HIV Agents / metabolism
  • Anti-HIV Agents / pharmacology
  • Binding Sites
  • Cell Fusion
  • Cell Line
  • Cell Migration Inhibition
  • Chemokine CXCL12
  • Chemokines / chemistry*
  • Chemokines / metabolism
  • Chemokines, CXC / antagonists & inhibitors
  • Chemokines, CXC / physiology
  • HIV-1 / pathogenicity
  • Humans
  • Molecular Sequence Data
  • Peptide Fragments / chemistry*
  • Peptide Fragments / metabolism
  • Peptide Fragments / physiology
  • Receptors, CXCR4 / antagonists & inhibitors*
  • Receptors, CXCR4 / metabolism
  • Receptors, CXCR4 / physiology
  • Receptors, CXCR5
  • Receptors, Chemokine
  • Receptors, Cytokine / antagonists & inhibitors
  • Receptors, Cytokine / metabolism
  • Signal Transduction


  • Anti-HIV Agents
  • CXCL12 protein, human
  • CXCR5 protein, human
  • Chemokine CXCL12
  • Chemokines
  • Chemokines, CXC
  • Peptide Fragments
  • Receptors, CXCR4
  • Receptors, CXCR5
  • Receptors, Chemokine
  • Receptors, Cytokine
  • vMIP-II