RSV fusion is mediated by F-protein, a major viral surface glycoprotein. CL-309623, a specific inhibitor of RSV, interacts tightly with F-protein, which results in a hydrophobic environment at the binding site. The binding is selective for F-protein and does not occur with G-protein, a surface glycoprotein that facilitates the binding of RSV to target cells, or with lipid membranes at concentrations in the sub-millimolar range. Using an assay based on the relief of self-quenching of octadecyl rhodamine (R18) incorporated in the RSV envelope, we show that the virus fuses efficiently with large unilamellar vesicles containing cholesterol, in the absence of specific receptor analogs. Fusion of cp-52, a mutant virus lacking the G and SH surface glycoproteins, with vesicles is inhibited by CL-309623 and RFI-641 due to specific interactions of the inhibitor(s) with the fusion protein. Both virus-vesicle and virus-cell fusion are inhibited with equal potency. The formation of the binary complex of CL-309623 with F-protein in its native state, resulting in the inhibition of fusion and entry of virus, is a prerequisite for the observed anti-RSV activity in cell cultures.

2002-03-01·Antimicrobial Agents and Chemotherapy2区 · 医学

RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

2区 · 医学

Article

作者: Raifeld, Yuri E. ; O'Connell, John F. ; Nikitenko, Antonia A. ; Feld, Boris ; Buklan, Aron ; Prince, Gregory ; Weiss, William J. ; O'Hara, Bryan ; Jones, Thomas R. ; Wyde, Philip ; Hu, William ; Huntley, Clayton C. ; Quartuccio, Susan ; Murphy, Timothy ; Gazumyan, Anna

ABSTRACTHuman respiratory syncytial virus (RSV), a paramyxovirus, is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. RFI-641 is a novel anti-RSV agent with potent in vitro and in vivo activity. RFI-641 is active against both RSV type A and B strains. The viral specificity and the large therapeutic window of RFI-641 (>100-fold) indicate that the antiviral activity of the compound is not due to adverse effects on normal cells. The potent in vitro activity of RFI-641 can be translated to efficacy in vivo: RFI-641 is efficacious when administered prophylactically by the intranasal route in mice, cotton rats, and African green monkeys. RFI-641 is also efficacious when administered therapeutically (24 h postinfection) in the monkey model. Mechanism of action studies indicate that RFI-641 blocks viral F protein-mediated fusion and cell syncytium formation.

2001-07-01·Chemistry & Biology

RFI-641 inhibits entry of respiratory syncytial virus via interactions with fusion protein

Article

作者: Anna Gazumyan ; Antonia Nikitenko ; Girija Krishnamurthy ; Vladimir Razinkov ; George Ellestad

BACKGROUNDRFI-641, a small dendrimer-like compound, is a potent and selective inhibitor of respiratory syncytial virus (RSV), which is currently a clinical candidate for the treatment of upper and lower respiratory tract infections caused by RSV. RFI-641 inhibits RSV growth with an IC(50) value of 50 nM and prevents syncytia formation in tissue culture. RSV contains of three surface glycoproteins, a small hydrophobic (SH) protein of unknown function, and attachment (G) and fusion (F) proteins that enable binding and fusion of virus, respectively, with target cells. Because of their role in attachment and fusion, the G and F surface proteins are prominent targets for therapeutic intervention. RFI-641 was previously shown to bind purified preparations of RSV fusion protein. Based on this observation, in conjunction with the biological results, it was speculated that the fusion event might be the target of these inhibitors.RESULTSA fusion assay based upon the relief of self-quenching of octadecyl rhodamine R18 was used to determine effects of the inhibitors on binding and fusion of RSV. The results show that RFI-641 inhibits both RSV-cell binding and fusion events. The inhibition of RSV is mediated via binding to the fusion protein on the viral surface. A closely related analog, WAY-158830, which is much less active in the virus-infectivity assay does not inhibit binding and fusion of RSV with Vero cells.CONCLUSIONSRFI-641, an in vivo active RSV inhibitor, is shown to inhibit both binding and fusion of RSV with cells, events that are early committed steps in RSV entry and pathogenicity. The results described here demonstrate that a non-peptidic, small molecule can inhibit binding and fusion of enveloped virus specifically via interaction with the viral fusion protein.

100 项与 RFI-641 相关的药物交易

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