title: Neomycin B-arginine conjugate, a novel HIV-1 Tat antagonist: synthesis and anti-HIV activities.
abstract: HIV-1 transactivating protein Tat is essential for virus replication and progression of HIV disease. HIV-1 Tat stimulates transactivation by binding to HIV-1 transactivator responsive element (TAR) RNA, and while secreted extracellularly, it acts as an immunosuppressor, an activator of quiescent T-cells for productive HIV-1 infection, and by binding to CXC chemokine receptor type 4 (CXCR4) as a chemokine analogue. Here we present a novel HIV-1 Tat antagonist, a neomycin B-hexaarginine conjugate (NeoR), which inhibits Tat transactivation and antagonizes Tat extracellular activities, such as increased viral production, induction of CXCR4 expression, suppression of CD3-activated proliferation of lymphocytes, and upregulation of the CD8 receptor. Moreover, Tat inhibits binding of fluoresceine isothiocyanate (FITC)-labeled NeoR to human peripheral blood mononuclear cells (PBMC), indicating that Tat and NeoR bind to the same cellular target. This is further substantiated by the finding that NeoR competes with the binding of monoclonal Abs to CXCR4. Furthermore, NeoR suppresses HIV-1 binding to cells. Importantly, NeoR accumulates in the cell nuclei and inhibits the replication of M- and T-tropic HIV-1 laboratory isolates (EC(50) = 0.8-5.3 microM). A putative model structure for the TAR-NeoR complex, which complies with available experimental data, is presented. We conclude that NeoR is a multitarget HIV-1 inhibitor; the structure, and molecular modeling and dynamics, suggest its binding to TAR RNA. NeoR inhibits HIV-1 binding to cells, partially by blocking the CXCR4 HIV-1 coreceptor, and it antagonizes Tat functions. NeoR is therefore an attractive lead compound, capable of interfering with different stages of HIV infection and AIDS pathogenesis.
authors.affiliation: Department of Organic Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Litovchick
authors.forename: A
authors.initials: A
authors.lastname: Lapidot
authors.forename: M
authors.initials: M
authors.lastname: Eisenstein
authors.forename: A
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: G
authors.initials: G
authors.lastname: Borkow
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001120:Arginine / Q000494:pharmacology; D001665:Binding Sites / Q000187:drug effects; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000096:biosynthesis / Q000378:metabolism; D002478:Cells, Cultured; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005456:Fluorescent Dyes / Q000378:metabolism; D005601:Framycetin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D016325:HIV Long Terminal Repeat / Q000187:drug effects; D015497:HIV-1 / Q000187:drug effects* / Q000254:growth & development; D006801:Humans; D007166:Immunosuppressive Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D020298:U937 Cells; D015854:Up-Regulation / Q000187:drug effects; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D015704:CD4 Antigens; D016827:CD8 Antigens; D005456:Fluorescent Dyes; D015696:Gene Products, tat; D007166:Immunosuppressive Agents; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C444521:neomycin B-arginine conjugate NeoR; D054322:tat Gene Products, Human Immunodeficiency Virus; D005601:Framycetin; D001120:Arginine