Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines

Naiming Zhou, Zhaowen Luo, Jiansong Luo, Xuejun Fan, Mark Cayabyab, Megumi Hiraoka, Dongxiang Liu, Xiaobing Han, James Pesavento, Chang Zhi Dong, Youli Wang, Jing An, Hideko Kaji, Joseph G. Sodroski, Ziwei Huang

Research output: Contribution to journalArticle

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Abstract

Chemokine receptor CXCR4 plays an important role in the immune system and the cellular entry of human immunodeficiency virus type 1 (HIV-1). To probe the stereospecificity of the CXCR4-ligand interface, D-amino acid peptides derived from natural chemokines, viral macrophage inflammatory protein II (vMIP-II) and stromal cell-derived factor-1α (SDF-1α), were synthesized and found to compete with 125I-SDF-1α and monoclonal antibody 12G5 binding to CXCR4 with potency and selectivity comparable with or higher than their L-peptide counterparts. This was surprising because of the profoundly different side chain topologies between D- and L-enantiomers, which circular dichroism spectroscopy showed adopt mirror image conformations. Further direct binding experiments using D-peptide labeled with fluorescein (designated as FAM-DV1) demonstrated that D- and L-peptides shared similar or at least overlapping binding site(s) on the CXCR4 receptor. Structure-activity analyses of related peptide analogs of mixed chiralities or containing alanine replacements revealed specific residues at the N-terminal half of the peptides as key binding determinants. Acting as CXCR4 antagonists and with much higher biological stability than L-counterparts, the D-peptides showed significant activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. These results show the remarkable stereochemical flexibility of the CXCR4-peptide interface. Further studies to understand the mechanism of this unusual feature of the CXCR4 binding surface might aid the development of novel CXCR4-binding molecules like the D-peptides that have high affinity and stability.

Original languageEnglish (US)
Pages (from-to)17476-17485
Number of pages10
JournalJournal of Biological Chemistry
Volume277
Issue number20
DOIs
StatePublished - May 17 2002

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Virus Internalization
Stereochemistry
Viruses
Chemokines
HIV-1
Peptides
Chemokine CXCL12
CXCR4 Receptors
Circular dichroism spectroscopy
Macrophage Inflammatory Proteins
Enantiomers
Chemokine Receptors
Chirality
Immune system
Viral Proteins
Circular Dichroism
Fluorescein
Alanine
Conformations
Immune System

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines. / Zhou, Naiming; Luo, Zhaowen; Luo, Jiansong; Fan, Xuejun; Cayabyab, Mark; Hiraoka, Megumi; Liu, Dongxiang; Han, Xiaobing; Pesavento, James; Dong, Chang Zhi; Wang, Youli; An, Jing; Kaji, Hideko; Sodroski, Joseph G.; Huang, Ziwei.

In: Journal of Biological Chemistry, Vol. 277, No. 20, 17.05.2002, p. 17476-17485.

Research output: Contribution to journalArticle

Zhou, N, Luo, Z, Luo, J, Fan, X, Cayabyab, M, Hiraoka, M, Liu, D, Han, X, Pesavento, J, Dong, CZ, Wang, Y, An, J, Kaji, H, Sodroski, JG & Huang, Z 2002, 'Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines', Journal of Biological Chemistry, vol. 277, no. 20, pp. 17476-17485. https://doi.org/10.1074/jbc.M202063200
Zhou, Naiming ; Luo, Zhaowen ; Luo, Jiansong ; Fan, Xuejun ; Cayabyab, Mark ; Hiraoka, Megumi ; Liu, Dongxiang ; Han, Xiaobing ; Pesavento, James ; Dong, Chang Zhi ; Wang, Youli ; An, Jing ; Kaji, Hideko ; Sodroski, Joseph G. ; Huang, Ziwei. / Exploring the stereochemistry of CXCR4-peptide recognition and inhibiting HIV-1 entry with D-peptides derived from chemokines. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 20. pp. 17476-17485.
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AU - Fan, Xuejun

AU - Cayabyab, Mark

AU - Hiraoka, Megumi

AU - Liu, Dongxiang

AU - Han, Xiaobing

AU - Pesavento, James

AU - Dong, Chang Zhi

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AB - Chemokine receptor CXCR4 plays an important role in the immune system and the cellular entry of human immunodeficiency virus type 1 (HIV-1). To probe the stereospecificity of the CXCR4-ligand interface, D-amino acid peptides derived from natural chemokines, viral macrophage inflammatory protein II (vMIP-II) and stromal cell-derived factor-1α (SDF-1α), were synthesized and found to compete with 125I-SDF-1α and monoclonal antibody 12G5 binding to CXCR4 with potency and selectivity comparable with or higher than their L-peptide counterparts. This was surprising because of the profoundly different side chain topologies between D- and L-enantiomers, which circular dichroism spectroscopy showed adopt mirror image conformations. Further direct binding experiments using D-peptide labeled with fluorescein (designated as FAM-DV1) demonstrated that D- and L-peptides shared similar or at least overlapping binding site(s) on the CXCR4 receptor. Structure-activity analyses of related peptide analogs of mixed chiralities or containing alanine replacements revealed specific residues at the N-terminal half of the peptides as key binding determinants. Acting as CXCR4 antagonists and with much higher biological stability than L-counterparts, the D-peptides showed significant activity in inhibiting the replication of CXCR4-dependent HIV-1 strains. These results show the remarkable stereochemical flexibility of the CXCR4-peptide interface. Further studies to understand the mechanism of this unusual feature of the CXCR4 binding surface might aid the development of novel CXCR4-binding molecules like the D-peptides that have high affinity and stability.

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