title: Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection.
abstract: The G-protein coupled receptor CXCR4 is a co-receptor for HIV-1 infection and is involved in signaling cell migration and proliferation. In a previous study of non-peptide, guanide-based CXCR4-binding compounds, spermine and spermidine phenylguanides inhibited HIV-1 entry at low micromolar concentrations. Subsequently, crystal structures of CXCR4 were used to dock a series of naphthylguanide derivatives of the polyamines spermidine and spermine. Synthesis and evaluation of the naphthylguanide compounds identified our best compound, spermine tris-1-naphthylguanide, which bound CXCR4 with an IC(50) of 40 nM and inhibited the infection of TZM-bl cells with X4, but not R5, strains of HIV-1 with an IC(50) of 50-100 nM.
authors: Department of Chemistry & Biochemistry, 155 Chemistry & Biochemistry Building, Montana State University, Bozeman, MT 59717, USA. roycew@montana.edu
authors: Royce A
authors: RA
authors: Wilkinson
authors: Seth H
authors: SH
authors: Pincus
authors: Kejing
authors: K
authors: Song
authors: Joyce B
authors: JB
authors: Shepard
authors: Alan J
authors: AJ
authors: Weaver
authors: Mohamed E
authors: ME
authors: Labib
authors: Martin
authors: M
authors: Teintze
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001645:Biguanides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D019380:Anti-HIV Agents; D001645:Biguanides; D019718:Receptors, CXCR4