title: Identification of a D-amino acid decapeptide HIV-1 entry inhibitor.
abstract: Entry of human immunodeficiency virus type 1 (HIV-1) virion into host cells involves three major steps, each being a potential target for the development of entry inhibitors: gp120 binding to CD4, gp120-CD4 complex interacting with a coreceptor, and gp41 refolding to form a six-helix bundle. Using a D-amino acid decapeptide combinatorial library, we identified peptide dC13 as having potent HIV-1 fusion inhibitory activity, and effectively inhibiting infection by several laboratory-adapted and primary HIV-1 strains. While dC13 did not block binding of gp120 to CD4, nor disrupt the gp41 six-helix bundle formation, it effectively blocked the binding of an anti-CXCR4 monoclonal antibody and chemokine SDF-1alpha to CXCR4-expressing cells. However, because R5-using primary viruses were also neutralized, the antiviral activity of dC13 implies additional mode(s) of action. These results suggest that dC13 is a useful HIV-1 coreceptor antagonist for CXCR4 and, due to its biostability and simplicity, may be of value for developing a new class of HIV-1 entry inhibitors.
authors.affiliation: Torrey Pines Institute for Molecular Studies, 3550 General Atomics Court, San Diego, CA 92121, USA.
authors.forename: César
authors.initials: C
authors.lastname: Boggiano
authors.forename: Shibo
authors.initials: S
authors.lastname: Jiang
authors.forename: Hong
authors.initials: H
authors.lastname: Lu
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhao
authors.forename: Shuwen
authors.initials: S
authors.lastname: Liu
authors.forename: James
authors.initials: J
authors.lastname: Binley
authors.forename: Sylvie E
authors.initials: SE
authors.lastname: Blondelle
mesh_terms: D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000037:antagonists & inhibitors; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments; D019151:Peptide Library; D019718:Receptors, CXCR4 / Q000187:drug effects; D013601:T-Lymphocytes / Q000821:virology
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D023581:HIV Fusion Inhibitors; D009842:Oligopeptides; D010446:Peptide Fragments; D019151:Peptide Library; D019718:Receptors, CXCR4; C513342:acetyl-arginyl-arginyl-methionyl-tyrosyl-arginyl-arginyl-isoleucyl-tyrosyl-arginyl-argininamide