title: Structure-function study and anti-HIV activity of synthetic peptide analogues derived from viral chemokine vMIP-II.
abstract: The viral macrophage inflammatory protein II (vMIP-II) shows a broad spectrum interaction with both CC and CXC chemokine receptors including CCR5 and CXCR4, two principal coreceptors for the cellular entry of human immunodeficiency virus type 1 (HIV-1). Recently, we have shown that a synthetic peptide derived from the N-terminus of vMIP-II, designated as V1, is a potent antagonist of CXCR4 but not CCR5 [Zhou, N., et al. (2000) Biochemistry 39, 3782-3787]. In this study, we synthesized a series of new peptides derived from other regions of vMIP-II and characterized their binding activities with both CXCR4 and CCR5. The results provided further support for the notion that the N-terminus of vMIP-II is the major determinant for CXCR4 recognition and that vMIP-II probably interacts with other chemokine receptors such as CCR5 with different sequence and conformational determinants. To understand the structure-function relationship of V1 peptide, its solution conformation was studied using circular dichroism spectroscopy, which showed a random conformation similar to that of the corresponding N-terminus in native vMIP-II. In addition, we synthesized a series of mutant analogues of V1 containing alanine, glycine, or phenylalanine substitution at various positions. Residues Val-1, Arg-7, and Lys-9 of V1 peptide were found to be critical for receptor interaction, because single alanine replacement at these positions dramatically decreased peptide binding to CXCR4. In contrast, alanine or phenylalanine substitution at Cys-11 led to significant enhancement in peptide affinity for CXCR4. Finally, we showed that V1 peptide inhibits HIV-1 replication in CXCR4(+) T-cell lines. These studies provide new insights into the structure-function relationship of V1 peptide and demonstrate that this peptide may be a lead for the development of therapeutic agents.
authors.affiliation: Kimmel Cancer Center and Department of Biochemistry and Molecular Pharmacology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA. zhuang@nana.jci.tju.edu
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
authors.forename: X
authors.initials: X
authors.lastname: Fan
authors.forename: N
authors.initials: N
authors.lastname: Zhou
authors.forename: M
authors.initials: M
authors.lastname: Hiraoka
authors.forename: J
authors.initials: J
authors.lastname: Luo
authors.forename: H
authors.initials: H
authors.lastname: Kaji
authors.forename: Z
authors.initials: Z
authors.lastname: Huang
mesh_terms: D000409:Alanine / Q000235:genetics; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002460:Cell Line; D018925:Chemokines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D003545:Cysteine / Q000235:genetics; D003588:Cytopathogenic Effect, Viral / Q000187:drug effects; D015726:Giant Cells / Q000187:drug effects; D005998:Glycine / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010649:Phenylalanine / Q000235:genetics; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000378:metabolism; D012996:Solutions; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
chemical_list: D019380:Anti-HIV Agents; D018925:Chemokines; D010446:Peptide Fragments; D010455:Peptides; D019718:Receptors, CXCR4; D012996:Solutions; C108059:vMIP-II; D010649:Phenylalanine; D003545:Cysteine; D000409:Alanine; D005998:Glycine