Inhibition of respiratory syncytial virus by a new class of
                        chemotherapeutic agents

Aulabaugh, Ann; Ding, Wei‐Qun; Ellestad, George A.; Gazumuan, A.; Hess, CW; Krishnamurthy, Girija; Mitsner, B. I.; Zaccardi, J.

doi:10.1358/dof.2000.025.03.572014

Cited by 14 publications

(13 citation statements)

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“…Possible explanations could be related to the pathogenesis of the virus in this animal model and/or the mechanism of action of BMS-433771 consisting of inhibition of the early step of membrane fusion. Interestingly, similar findings were obtained for RFI-641 (CL387626), another small-molecule RSV fusion inhibition that targets the F protein (3,10,12). Although it was effective when administered intranasally to cotton rats 1 h prior to virus inoculation, there was no demonstrable therapeutic effect by RFI-641 when administered postinfection in this small animal model (40).…”

Section: Discussionsupporting

confidence: 70%

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Cianci

Genovesi

Lamb

et al. 2004

Antimicrob Agents Chemother

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). In this report, the in vivo efficacy of BMS-433771 against RSV was further examined in the BALB/c mouse and cotton rat host models of infection. By using the Long strain of RSV, prophylactic efficacy via oral dosing was observed in both animal models. A single oral dose, administered 1 h prior to intranasal RSV inoculation, was as effective against infection as a 4-day b.i.d. dosing regimen in which the first oral dose was given 1 h prior to virus inoculation. Results of dose titration experiments suggested that RSV infection was more sensitive to inhibition by BMS-433771 treatment in the BALB/c mouse host than in the cotton rat. This was reflected by the pharmacokinetic and pharmacodynamic analysis of the efficacy data, where the area under the concentration-time curve required to achieve 50% of the maximum response was ϳ7.5-fold less for mice than for cotton rats. Inhibition of RSV by BMS-433771 in the mouse is the result of F1-mediated inhibition, as shown by the fact that a virus selected for resistance to BMS-433771 in vitro and containing a single amino acid change in the F1 region was also refractory to treatment in the mouse host. BMS-433771 efficacy against RSV infection was also demonstrated for mice that were chemically immunosuppressed by cyclophosphamide treatment, indicating that compound inhibition of the virus did not require an active host immune response.

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Section: Discussionsupporting

confidence: 70%

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Cianci

Genovesi

Lamb

et al. 2004

Antimicrob Agents Chemother

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“…25). RFI-641 has been shown to bind to the F 1 N-terminal heptad repeat (21). However, we have observed that this compound does not bind to the same site as BMS-433771 (unpublished data).…”

Section: A Radiolabeled Analog Of the Rsv Fusion Inhibitor Bms-433771mentioning

confidence: 78%

Targeting a binding pocket within the trimer-of-hairpins: Small-molecule inhibition of viral fusion

Cianci

Langley

Dischino

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

103

100

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Trimeric class I virus fusion proteins undergo a series of conformational rearrangements that leads to the association of C-and N-terminal heptad repeat domains in a ''trimer-of-hairpins'' structure, facilitating the apposition of viral and cellular membranes during fusion. This final fusion hairpin structure is sustained by protein-protein interactions, associations thought initially to be refractory to small-molecule inhibition because of the large surface area involved. By using a photoaffinity analog of a potent respiratory syncytial virus fusion inhibitor, we directly probed the interaction of the inhibitor with its fusion protein target. Studies have shown that these inhibitors bind within a hydrophobic cavity formed on the surface of the N-terminal heptad-repeat trimer. In the fusogenic state, this pocket is occupied by key amino acid residues from the C-terminal heptad repeat that stabilize the trimer-of-hairpins structure. The results indicate that a low-molecular-weight fusion inhibitor can interfere with the formation or consolidation of key structures within the hairpin moiety that are essential for membrane fusion. Because analogous cavities are present in many class I viruses, including HIV, these results demonstrate the feasibility of this approach as a strategy for drug discovery.

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“…A specific inhibitor of RSV, CL387626, was identified and subsequently shown to have activity in the nanomolar range against a wide variety of RSV clinical and laboratory strains (1,4). That compound demonstrated an excellent safety profile in tissue culture cells (selective index of 1,500 in proliferating HEP-2 and Vero cells) and showed encouraging in vivo activity in RSV-infected cotton rats (28).…”

Section: Discussionmentioning

confidence: 99%

“…A number of small-molecule inhibitors of RSV have been identified, but to date none are clinically approved (7,23). RFI-641 is the result of a chemical optimization of CL387626 (1,4,28), a compound that inhibits RSV fusion and demonstrates antiviral activity in vitro and in vivo. We report here on the in vitro activity, mechanism, and in vivo activity of RFI-641.…”

mentioning

confidence: 99%

RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

Huntley

Weiss

Gazumyan

et al. 2002

Antimicrob Agents Chemother

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Human 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.Human respiratory syncytial virus (RSV), a member of the Paramyxoviridae family (18), is a major cause of acute upper and lower respiratory tract infections in infants, young children, and adults. Serological evidence indicates that approximately 95% of children have been exposed to RSV by 2 years of age, and 100% of children have been exposed by the time they reach adulthood (8). In a given year, around 91,000 infants are hospitalized with RSV infection in the United States. These infections are responsible for 40 to 50% of hospitalizations for pediatric bronchiolitis and 25% of hospitalizations for pediatric pneumonia (8,15). Since the immune response to RSV infection is not protective, RSV infections reoccur throughout adulthood. In adults and older children, RSV infection has been associated with upper respiratory infection, tracheobronchitis, and otitis media. However, RSV in the institutionalized elderly can be more serious and is characterized by severe pneumonia and mortality rates of up to 20 and 78%, respectively (5, 6). Adults with a previous history of heart or lung conditions are at a high risk for RSV infection. The infection has been linked to exacerbation of patients with chronic obstructive pulmonary disease. Significant mortality has been observed in immunocompromised patients, particularly those undergoing bone marrow transplantation. Regular outbreaks of RSV are well characterized and predictable, occurring between October and May each year with peak occurrences in January and February. Ribavirin is the only commercially available agent used to treat RSV infection (2). The utilization of ribavirin is limited due to efficacy and toxicity concerns as well as the very long treatment regimen required for its delivery by aerosol inhalation (19). Protective antibodies (14, 27), indicated for prophylaxis in high-risk children, are administered intravenously (RespiGam) or intramuscularly (Synagis). A number of small-molecule inhibitors of RSV have been identified, but to date none are clinically approved (7, 23). RFI-641 is the result of a chemical optimization of CL387626 (1, 4, 28), a compound that inhi...

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Inhibition of respiratory syncytial virus by a new class of chemotherapeutic agents

Cited by 14 publications

References 0 publications

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Oral Efficacy of a Respiratory Syncytial Virus Inhibitor in Rodent Models of Infection

Targeting a binding pocket within the trimer-of-hairpins: Small-molecule inhibition of viral fusion

RFI-641, a Potent Respiratory Syncytial Virus Inhibitor

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