title: A double-mimetic peptide efficiently neutralizes HIV-1 by bridging the CD4- and coreceptor-binding sites of gp120.
abstract: The HIV-1 envelope glycoprotein binds cooperatively to its cellular receptor CD4 and a coreceptor, principally CXCR4 or CCR5. We have previously improved a natural amino-acid form of a scorpion toxin-derived CD4-mimetic peptide and in parallel generated sulfopeptide mimetics of the CCR5 amino terminus. Here we show that some fusions of these CCR5- and CD4-mimetic peptides, expressed as immunoadhesins, neutralize HIV-1 more efficiently than CD4-Fc or equimolar mixtures of immunoadhesin forms of each peptide. Specifically, double-mimetic peptides with linkers of 11 amino acids or greater, and with the CCR5-mimetic component preceding the CD4-mimetic component, were more efficient than constructs with shorter linkers or in a reverse orientation. The potency of these constructs derives from (i) their ability to simultaneously and cooperatively bind the CD4- and CCR5-binding sites of a single gp120 monomer of the HIV-1 envelope glycoprotein trimer and (ii) the ability of the CCR5-mimetic component to prevent the CD4-mimetic peptide from promoting infection when cellular CD4 is limiting. Thus, there is a significant advantage to simultaneously targeting both conserved regions of the HIV-1 envelope glycoprotein.
  
  
  OBJECTIVE
  This report describes a novel class of peptides that potently inhibit HIV-1 entry. These peptides simultaneously target the receptor- and coreceptor-binding sites of the HIV-1 envelope glycoprotein gp120. Peptides of this class overcome key limitations of inhibitors that target only one gp120 binding region and illustrate the utility of binding the sulfotyrosine-binding pockets of gp120.
authors.affiliation: Department of Infectious Diseases, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Quinlan
authors.forename: Vinita R
authors.initials: VR
authors.lastname: Joshi
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Gardner
authors.forename: Kourosh H
authors.initials: KH
authors.lastname: Ebrahimi
authors.forename: Michael
authors.initials: M
authors.lastname: Farzan
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015699:HIV Envelope Protein gp120 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D010455:Peptides / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015728:Receptors, HIV / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D010455:Peptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D015728:Receptors, HIV