Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate, Part 1:  Improving the Pharmacokinetic Profile Using the Structure−Property Relationship

Bonfanti, Jean‐François; Doublet, Frédéric; Fortin, Jérôme; Lacrampe, Jean; Guillemont, Jérôme; Müller, Philippe; Quéguiner, Laurence; Arnoult, Éric; Gevers, Tom; Janssens, Peggy; Szel, Heidi; Willebrords, R.; Timmerman, Philip; Wuyts, Koen; Janssens, Frans; Sommen, Cois; Wigerinck, Piet; Andries, Koen

doi:10.1021/jm070143x

Cited by 43 publications

(48 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although extremely potent when tested in both tissue culture and the lungs of cotton rats, JNJ-2408068 was found to have long tissue retention, making it unsatisfactory for further development as an antiviral compound [90, 92]. Lead optimization guided by molecular modeling resulted in a morpholinopropyl derivative, TMC353121, which retained the potency of its predecessor, but lacked its long tissue retention [90, 91]. TMC353121 inhibits both virus-cell and cell-cell fusion in vitro , and maintains 50% effectiveness when added to cells as late as 15 h post-inoculation [93].…”

Section: Advances In Rsv Antiviral Drug Developmentmentioning

confidence: 99%

Targeting RSV with Vaccines and Small Molecule Drugs

Costello¹,

Ray²,

Chaiwatpongsakorn³

et al. 2012

IDDT

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) is the most significant cause of pediatric respiratory infections. Palivizumab (Synagis®), a humanized monoclonal antibody, has been used successfully for a number of years to prevent severe RSV disease in at-risk infants. However, despite intense efforts, there is no approved vaccine or small molecule drug for RSV. As an enveloped virus, RSV must fuse its envelope with the host cell membrane, which is accomplished through the actions of the fusion (F) glycoprotein, with attachment help from the G glycoprotein. Because of their integral role in initiation of infection and their accessibility outside the lipid bilayer, these proteins have been popular targets in the discovery and development of antiviral compounds and vaccines against RSV. This review examines advances in the development of antiviral compounds and vaccine candidates.

show abstract

Section: Advances In Rsv Antiviral Drug Developmentmentioning

confidence: 99%

Targeting RSV with Vaccines and Small Molecule Drugs

Costello¹,

Ray²,

Chaiwatpongsakorn³

et al. 2012

IDDT

View full text Add to dashboard Cite

show abstract

“…The F (fusion) protein is crucial in this process and thus plays a critical role in establishing an infection. Several small molecule inhibitors of the fusion process have been identified [12][13][14][15][16][17], but most were discontinued for scientific or strategic reasons [18].…”

mentioning

confidence: 99%

“…The RSV fusion inhibitor TMC353121 has been developed from the precursor molecule JNJ-2408068 [17] using a molecular modelling approach. It maintains high activity (pEC50 9.9) and low cytotoxicity, while presenting a shorter retention time in the lung (lung t 1/2 25 h) [19].…”

mentioning

confidence: 99%

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Olszewska¹,

Ispas²,

Schnoeller³

et al. 2010

European Respiratory Journal

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) causes bronchiolitis in young children and common colds in adults. There is no licensed vaccine, and prophylactic treatment with palivizumab is very expensive and limited to high-risk infants. Ribavirin is used as an antiviral treatment in infants and immunosuppressed patients, and its use is limited due to side-effects, toxicity to the recipient and staff, and evidence of marginal clinical efficacy. Therefore, we studied the in vivo kinetics, and the antiviral and protective properties of a novel candidate for RSV disease treatment.The drug is a small molecule (TMC353121) discovered by screening for fusion inhibitory properties against RSV in a cellular infection model. The pharmacokinetics of TMC353121 was studied in BALB/c mice and antiviral effects determined by testing viral loads in lung tissue by quantitative RT-PCR and plaque assay after intranasal RSV infection.At doses of 0.25-10 mg?kg -1 , TMC353121 significantly reduced viral load, bronchoalveolar lavage cell accumulation and the severity of lung histopathological change after infection. Treatment remained effective if started within 48 h of infection, but was ineffective thereafter. Therefore, TMC353121 is a novel potent antiviral drug, in vivo reducing RSV replication and inhibiting consequential lung inflammation, with a great potential for further clinical development.

show abstract

“…Like VP-14637, JNJ-2408068 also inhibits RSV fusion by binding to ahydrophobic pocket that forms between HAR and HAR during the assembly of 6-HB in the inner core of F protein and interacting simultaneously with both the HRA and HRB domains [18,51]. However, JNJ-2408068 was later found to be unsuitable for further development because of its long tissue retention in rats, dogs and monkeys [58]. Further optimization of JNJ-2408068 resulted in identification a better drug candidate with improved pharmacokinetic profile, TMC-353121, a morpholinopropyl derivative (Figure 3) [59].…”

Section: Small-molecule Rsv Entry Inhibitors Targeting F Proteinmentioning

confidence: 99%

Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein

Sun

Pan²,

Jiang

et al. 2013

Viruses

View full text Add to dashboard Cite

Human respiratory syncytial virus (RSV) is the main viral cause of respiratory tract infection in infants as well as some elderly and high-risk adults with chronic pulmonary disease and the severely immunocompromised. So far, no specific anti-RSV therapeutics or effective anti-RSV vaccines have been reported. Only one humanized monoclonal antibody, Palivizumab, has been approved for use in high-risk infants to prevent RSV infection. Ribavirin is the only drug licensed for therapy of RSV infection, but its clinical use is limited by its nonspecific anti-RSV activity, toxic effect, and relatively high cost. Therefore, development of novel effective anti-RSV therapeutics is urgently needed. The RSV envelope glycoprotein F plays an important role in RSV fusion with, and entry into, the host cell and, consequently, serves as an attractive target for developing RSV entry inhibitors. This article reviews advances made in studies of the structure and function of the F protein and the development of RSV entry inhibitors targeting it.

show abstract

Selection of a Respiratory Syncytial Virus Fusion Inhibitor Clinical Candidate, Part 1: Improving the Pharmacokinetic Profile Using the Structure−Property Relationship

Cited by 43 publications

References 16 publications

Targeting RSV with Vaccines and Small Molecule Drugs

Targeting RSV with Vaccines and Small Molecule Drugs

Antiviral and lung protective activity of a novel respiratory syncytial virus fusion inhibitor in a mouse model

Respiratory Syncytial Virus Entry Inhibitors Targeting the F Protein

Contact Info

Product

Resources

About