Novel Dengue Virus NS2B/NS3 Protease Inhibitors

Wang, Hongmei; Bock, Stefanie; Snitko, Mariya; Berger, Thilo; Weidner, Thomas; Holloway, S A; Kanitz, Manuel; Diederich, Wibke E.; Steuber, H.; Walter, Christof; Hofmann, Daniela; Weißbrich, Benedikt; Spannaus, Ralf; Acosta, Eliana G.; Bartenschlager, Ralf; Engels, Bernd; Schirmeister, Tanja; Bodem, Jochen

doi:10.1128/aac.03543-14

Cited by 120 publications

(121 citation statements)

References 36 publications

(37 reference statements)

Supporting

Mentioning

107

Contrasting

Unclassified

Order By: Relevance

“…There are globally known four antigenically distinct serotypes (DENV 1, 2, 3, and 4) exist, and they are mostly prevalent in dengue‐endemic regions such as Asia, Africa, and America . All these serotypes share more than 70% sequence homology with GC conservation regions, and infections caused by these serotypes also share common dengue viral symptoms .…”

Section: Introductionmentioning

confidence: 99%

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Bhowmick

Alissa

Wabaidur

et al. 2020

J of Molecular Recognition

View full text Add to dashboard Cite

Dengue infection is the most common arthropod-borne disease caused by dengue viruses, predominantly affecting millions of human beings annually. To find out promising chemical entities for therapeutic application in Dengue, in the current research, a multi-step virtual screening effort was conceived to screen out the entire "screening library" of the Asinex database. Initially, through "Lipinski rule of five" filtration criterion almost 0.6 million compounds were collected and docked with NS3-NS2B protein. Thereby, the chemical space was reduced to about 3500 compounds through the analysis of binding affinity obtained from molecular docking study in AutoDock Vina. Further, the "Virtual Screening Workflow" (VSW) utility of Schrödinger suite was used, which follows a stepwise multiple docking programs such as -high-throughput virtual screening (HTVS), standard precision (SP), and extra precision (XP) docking, and in postprocessing analysis the MM-GBSA based free binding energy calculation. Finally, five potent molecules were proposed as potential inhibitors for the dengue NS3-NS2B protein based on the investigation of molecular interactions map and protein-ligand fingerprint analyses. Different pharmacokinetics and drug-likeness parameters were also checked, which favour the potentiality of selected molecules for being drug-like candidates. The molecular dynamics (MD) simulation analyses of protein-ligand complexes were explained that NS3-NS2B bound with proposed molecules quite stable in dynamic states as observed from the root means square deviation (RMSD) and root means square fluctuation (RMSF) parameters. The binding free energy was calculated using MM-GBSA method from the MD simulation trajectories revealed that all proposed molecules possess such a strong binding affinity towards the dengue NS3-NS2B protein. Therefore, proposed molecules may be potential chemical components for effective inhibition of dengue NS3-NS2B protein subjected to experimental validation.

show abstract

Section: Introductionmentioning

confidence: 99%

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Bhowmick

Alissa

Wabaidur

et al. 2020

J of Molecular Recognition

View full text Add to dashboard Cite

show abstract

“…These efforts have resulted in identification of a variety of small molecules that inhibit viral replication through targeting distinct viral and host cellular functions (17)(18)(19). Small molecules that specifically target viral capsid assembly (20), NS3/2A proteases (21)(22)(23), NS3 RNA helicase (24), NS4B protein (25,26), NS5 methyltransferase (27), and RNA-dependent RNA polymerase (28,29) have been discovered, and the in vivo antiviral efficacies for four of these direct-acting antiviral (DAA) agents have been demonstrated in animal models (24,(30)(31)(32); however, none of them has reached human clinical trials. Balapiravir, a tri-isobutyrate ester prodrug of 4=-azidocytidine (R1479) that was originally developed for treatment of chronic hepatitis C virus (HCV) infection by Hoffmann-La Roche, is active against DENV in cultured cells.…”

mentioning

confidence: 99%

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

Guo

Julander

et al. 2016

J Virol

View full text Add to dashboard Cite

Although a highly effective vaccine is available, the number of yellow fever cases has increased over the past 2 decades, which highlights the pressing need for antiviral therapeutics. In a high-throughput screening campaign, we identified an acetic acid benzodiazepine (BDAA) compound which potently inhibits yellow fever virus (YFV). Interestingly, while treatment of YFV-infected cultures with 2 M BDAA reduced the virion production by greater than 2 logs, the compound was not active against 21 other viruses from 14 different viral families. Selection and genetic analysis of drug-resistant viruses revealed that replacement of the proline at amino acid 219 (P219) of the nonstructural protein 4B (NS4B) with serine, threonine, or alanine conferred YFV with resistance to BDAA without apparent loss of replication fitness in cultured mammalian cells. However, replacement of P219 with glycine conferred BDAA resistance with significant loss of replication ability. Bioinformatics analysis predicts that the P219 amino acid is localized at the endoplasmic reticulum lumen side of the fifth putative transmembrane domain of NS4B, and the mutation may render the viral protein incapable of interacting with BDAA. Our studies thus revealed an important role and the structural basis for the NS4B protein in supporting YFV replication. Moreover, in YFV-infected hamsters, oral administration of BDAA protected 90% of the animals from death, significantly reduced viral load by greater than 2 logs, and attenuated virus infection-induced liver injury and body weight loss. The encouraging preclinical results thus warrant further development of BDAA or its derivatives as antiviral agents to treat yellow fever. IMPORTANCEYellow fever is an acute viral hemorrhagic disease which threatens approximately 1 billion people living in tropical areas of Africa and Latin America. Although a highly effective yellow fever vaccine has been available for more than 7 decades, the low vaccination rate fails to prevent outbreaks in at-risk regions. It has been estimated that up to 1.7 million YFV infections occur in Africa each year, resulting in 29,000 to 60,000 deaths. Thus far, there is no specific antiviral treatment for yellow fever. To cope with this medical challenge, we identified a benzodiazepine compound that selectively inhibits YFV by targeting the viral NS4B protein. To our knowledge, this is the first report demonstrating in vivo safety and antiviral efficacy of a YFV NS4B inhibitor in an animal model. We have thus reached a critical milestone toward the development of specific antiviral therapeutics for clinical management of yellow fever. Y ellow fever is a mosquito-borne hemorrhagic disease that is frequently associated with jaundice and is caused by yellow fever virus (YFV) infection (1). Vaccination with attenuated YFV-17D vaccine is the most important measurement to prevent yellow fever. The vaccine is safe, affordable, and highly effective, and a single dose of the vaccine is sufficient to confer sustained immunity and lifelong p...

show abstract

“…Active siteÀdirected tetrapeptide and tripeptide inhibitors were synthesized to probe the dynamics of the DENV protease active site with different functional groups that compete with the substrate. These active site serine-trap inhibitors contained either boronic acid, trifluoromethylketone, or aldehyde as the electrophilic warhead (Schuller et al, 2011) and showed potent protease inhibitor activity against DENV-1À4 NS2B/NS3 protease as well as other flaviviral proteases, thus demonstrating that pan-dengue or pan-flaviviral protease inhibitors can be developed (Chu et al, 2015;Dwivedi et al, 2016;Pelliccia et al, 2017;Soares et al, 2018;Tan et al, 2018;Wu et al, 2015). In addition to targeting polyprotein processing, it has been shown that specific translational inhibitors can be developed.…”

Section: Polyprotein Processing and Translation Inhibitorsmentioning

confidence: 99%

Dengue Virus

Murugesan¹,

Mythreyee²

2020

Emerging and Reemerging Viral Pathogens

View full text Add to dashboard Cite

At some point in the past 2000À4000 years, DENVs moved out of the Asian jungle and into rural villages, where they were, and still are, transmitted to humans by peridomestic mosquitoes such as A. albopictus. Migration of people and commerce ultimately moved the viruses into larger villages, towns, and cities of tropical Asia, where the viruses were most likely transmitted sporadically by A. albopictus and possibly other closely related peridomestic Stegomyia species (Halstead, 2007). The slave trade and the resulting commerce were responsible for the introduction and the widespread distribution of an African mosquito, 284 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS 288 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS 292 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS 294 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS 296 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS 298 16. DENGUE VIRUS EMERGING AND REEMERGING VIRAL PATHOGENS

show abstract

Novel Dengue Virus NS2B/NS3 Protease Inhibitors

Cited by 120 publications

References 36 publications

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

Structure‐guided screening of chemical database to identify NS3‐NS2B inhibitors for effective therapeutic application in dengue infection

A Novel Benzodiazepine Compound Inhibits Yellow Fever Virus Infection by Specifically Targeting NS4B Protein

Dengue Virus

Contact Info

Product

Resources

About