Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor

Zheng, Xiufang; Gao, Lu; Wang, Lisha; Liang, Chengzhen; Wang, Baoxia; Liu, Yongfu; Feng, Song; Zhang, Bo; Zhou, Mingwei; Yu, Xin; Xiang, Kunlun; Chen, Li; Guo, Tao; Shen, Hong C.; Zou, Gang; Wu, Jim Zhen; Hua, Yun

doi:10.1021/acs.jmedchem.9b00654

Cited by 59 publications

(49 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1-3). Consistent with this, in a recent study, these residues of RSV F protein have also been documented to interact with Ziresovir, which has been reported as a promising RSV F protein inhibitor and currently in phase II clinical trials [20].…”

Section: Resultssupporting

confidence: 63%

Identification of Respiratory Syncytial Virus Fusion Protein Inhibitor: In silico Screening and Molecular Docking Approach

Alshaghdali

2021

JPRI

View full text Add to dashboard Cite

In young children, immunocompromised individuals, and elderly people, the respiratory syncytial virus (RSV) is the primary source of acute lower respiratory tract infection. Intervention with RSV-specific small-molecule antivirals may provide significant therapeutic potential. For virus entry, the RSV fusion protein (F) is crucial as it facilitates viral and hosts membrane fusion. To date, no approved vaccine or drug molecule is available to treat RSV. With this purpose, in the present study, virtual screening of a library of natural compounds against the active site of F protein was performed, followed by an in-depth molecular docking study of top-scored compounds. Selected hits ZINC8740013, ZINC4029781 and ZINC898642were found to strongly bind with RSV F protein relative to the other compounds as well as the control. The binding energy (BE) and inhibition constant for ‘ZINC8740013-RSV F’, ‘ZINC4029781-RSV F’, and ‘ZINC898642-RSVF’ complexes were found as ‘-7.8 kcal/mol and 63.27 µM’, ‘-7.7 kcal/mol and 19.04 µM’, and ‘-7.5 kcal/mol and 3.31 µM’, respectively. However, BE and inhibition constant of control (JNJ-53718678) with RSV F protein was found as -6.1 kcal/mol and 563.26 µM, respectively. Phe140 and Phe488 are the main interacting residues of RSV F protein with JNJ-53718678 and selected hit compounds. The finding of this study suggests that these hits can be utilized as the RSV Fprotein inhibitor to prevent the fusion of the viral envelope with the host cells. Further, bench work experiments are required to optimize these hit compounds as RSV Fprotein inhibitors.

show abstract

Section: Resultssupporting

confidence: 63%

Identification of Respiratory Syncytial Virus Fusion Protein Inhibitor: In silico Screening and Molecular Docking Approach

Alshaghdali

2021

JPRI

View full text Add to dashboard Cite

show abstract

“… 68 Last year, Ark Biosciences reported the successful completion of a phase II clinical trial of ziresovir (DB15145, −8.4 kcal/mol) in infants with respiratory syncytial virus (RSV) infection. 69 …”

Section: Resultsmentioning

confidence: 99%

Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study

Banerjee

Yadav

Banerjee

et al. 2021

J. Chem. Inf. Model.

View full text Add to dashboard Cite

COVID-19, an acute viral pneumonia, has emerged as a devastating pandemic. Drug repurposing allows researchers to find different indications of FDA-approved or investigational drugs. In this current study, a sequence of pharmacophore and molecular modeling-based screening against COVID-19 M pro (PDB: 6LU7) suggested a subset of drugs, from the Drug Bank database, which may have antiviral activity. A total of 44 out of 8823 of the most promising virtual hits from the Drug Bank were subjected to molecular dynamics simulation experiments to explore the strength of their interactions with the SARS-CoV-2 M pro active site. MD findings point toward three drugs (DB04020, DB12411, and DB11779) with very low relative free energies for SARS-CoV-2 M pro with interactions at His41 and Met49. MD simulations identified an additional interaction with Glu166, which enhanced the binding affinity significantly. Therefore, Glu166 could be an interesting target for structure-based drug design. Quantitative structural–activity relationship analysis was performed on the 44 most promising hits from molecular docking-based virtual screening. Partial least square regression accurately predicted the values of independent drug candidates’ binding energy with impressively high accuracy. Finally, the EC 50 and CC 50 of 10 drug candidates were measured against SARS-CoV-2 in cell culture. Nilotinib and bemcentinib had EC 50 values of 2.6 and 1.1 μM, respectively. In summary, the results of our computer-aided drug design provide a roadmap for rational drug design of M pro inhibitors and the discovery of certified medications as COVID-19 antiviral therapeutics.

show abstract

“…GS-5806 (presatovir), a drug blocking RSV fusion protein [165], has undergone several trials, studying its effects on both general population (NCT02135614) and HSCT recipients with RSV URTI (NCT02254408) and LRTI (NCT02254421); results have not yet been published. AK0529 (ziresovir) [166], an orally bioavailable RSV fusion protein inhibitor, is currently undergoing a phase 2 study on adults with RSV infection in China (NCT03699202), while a multicentric study on a pediatric population has been completed, with results upcoming (NCT02654171). ALX-0171, a trimeric nanobody that binds to the antigenic site II of the RSV F protein with high affinity, has proven superior in vitro neutralization to that of palivizumab.…”

Section: Management Of Crv Infectionsmentioning

confidence: 99%

Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients?

et al. 2019

View full text Add to dashboard Cite

Despite a plethora of studies demonstrating significant morbidity and mortality due to community-acquired respiratory viral (CRV) infections in intensively treated hematology patients, and despite the availability of evidence-based guidelines for the diagnosis and management of respiratory viral infections in this setting, there is no uniform inclusion of respiratory viral infection management in the clinical hematology routine. Nevertheless, timely diagnosis and systematic management of CRV infections in intensively treated hematology patients has a demonstrated potential to significantly improve outcome. We have briefly summarized the recently published data on CRV infection epidemiology, as well as guidelines on the diagnosis and management of CRV infections in patients intensively treated for hematological malignancies. We have also assessed available treatment options, as well as mentioned novel agents currently in development.

show abstract

Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor

Cited by 59 publications

References 20 publications

Identification of Respiratory Syncytial Virus Fusion Protein Inhibitor: In silico Screening and Molecular Docking Approach

Identification of Respiratory Syncytial Virus Fusion Protein Inhibitor: In silico Screening and Molecular Docking Approach

Drug Repurposing to Identify Nilotinib as a Potential SARS-CoV-2 Main Protease Inhibitor: Insights from a Computational and In Vitro Study

Are Community Acquired Respiratory Viral Infections an Underestimated Burden in Hematology Patients?

Contact Info

Product

Resources

About