Improved guanide compounds which bind the CXCR4 co-receptor and inhibit HIV-1 infection |
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Authors: | Royce A Wilkinson Seth H Pincus Kejing Song Joyce B Shepard Alan J Weaver Mohamed E Labib Martin Teintze |
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Institution: | 1. Department of Chemistry & Biochemistry, 155 Chemistry & Biochemistry Building, Montana State University, Bozeman, MT 59717, United States;2. Research Institute for Children, Children’s Hospital, New Orleans, LA 70118, United States;3. Department of Pediatrics, LSU Health Sciences Center, New Orleans, LA 70118, United States;4. Novaflux Biosciences, Inc., Princeton, NJ 08540, United States |
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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 IC50 of 40 nM and inhibited the infection of TZM-bl cells with X4, but not R5, strains of HIV-1 with an IC50 of 50–100 nM. |
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