A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication

Pambudi, Sabar; Kawashita, Norihito; Phanthanawiboon, Supranee; Omokoko, Magot Diata; Masrinoul, Promsin; Yamashita, Akifumi; Limkittikul, Kriengsak; Yasunaga, Teruo; Takagi, Tatsuya; Ikuta, Kazuyoshi; Kurosu, Takeshi

doi:10.1016/j.bbrc.2013.09.078

Cited by 53 publications

(34 citation statements)

References 20 publications

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“…It was previously reported that the small molecule SK-12 is an orthosteric inhibitor blocking NS2B-NS3 interactions [25]. Mutagenesis studies indicate that SK-12 interacts with the DENV NS3 residue at position 27, which is part of the pocket holding the NS2B residue L51 [25].…”

Section: Slc Assay With a Known Orthosteric Inhibitormentioning

confidence: 99%

“…Mutagenesis studies indicate that SK-12 interacts with the DENV NS3 residue at position 27, which is part of the pocket holding the NS2B residue L51 [25]. We first verified that SK-12 inhibited the SLC in a dose-dependent manner with an IC 50-SLC of 10 µM ( Figure 2A); at 40 µM SK-12 gave significant and robust inhibition of the SLC of NLuc-E66-stop/GCN with a signal/background (S/B) ratio (DMSO vs SK-12) of 8.4-fold ( Figure 2B).…”

Section: Slc Assay With a Known Orthosteric Inhibitormentioning

confidence: 99%

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Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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Recent outbreaks of Zika virus (ZIKV) highlight an urgent need for therapeutics.The protease complex NS2B-NS3 plays essential roles during flaviviral polyprotein processing, and thus represents an attractive drug target. Here, we developed a split luciferase complementation-based high-throughput screening assay to identify orthosteric inhibitors that directly target flavivirus NS2B-NS3 interactions. By screening a total of 2 816 approved and investigational drugs, we identified three potent candidates, temoporfin, niclosamide, and nitazoxanide, as flavivirus NS2B-NS3 interaction inhibitors with nanomolar potencies. Significantly, the most potent compound, temoporfin, not only inhibited ZIKV replication in human placental and neural progenitor cells, but also prevented ZIKV-induced viremia and mortality in mouse models. Structural docking suggests that temoporfin potentially binds NS3 pockets that hold critical NS2B residues, thus inhibiting flaviviral polyprotein processing in a non-competitive manner. As these drugs have already been approved for clinical use in other indications either in the USA or other countries, they represent promising and easily developed therapies for the management of infections by ZIKV and other flaviviruses.

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Section: Slc Assay With a Known Orthosteric Inhibitormentioning

confidence: 99%

Section: Slc Assay With a Known Orthosteric Inhibitormentioning

confidence: 99%

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

et al. 2017

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“…For example, one cyclopentapeptide was proposed as an inhibitor of the DENV2 NS2B/NS3 protease [21] , and MrIA, a type of conotoxin, was also determined to be an inhibitor for this protease [22] . Recently, varied types of potential inhibitors against the DENV2 NS2B/NS3 protease have been reported [11,[23][24][25][26][27][28] , but few inhibitors exhibited antiviral activities. Therefore, it is urgent to discover novel NS2B/NS3 protease inhibitors with high activities against dengue virus.…”

Section: Introductionmentioning

confidence: 99%

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Mao

et al. 2015

Acta Pharmacol Sin

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Aim: Dengue is a severe epidemic disease caused by dengue virus (DENV) infection, for which no effective treatment is available. The protease complex, consisting of nonstructural protein 3 (NS3) and its cofactor NS2B, plays a pivotal role in the replication of DENV, thus may be a potential target for anti-DENV drugs. Here, we report a novel inhibitor of DENV2 NS2B/NS3 protease and its antiviral action. Methods: An enzymatic inhibition assay was used for screening DENV2 NS2B/NS3 inhibitors. Cytotoxicity to BHK-21 cells was assessed with MTT assay. Antiviral activity was evaluated in BHK-21 cells transfected with Rlu-DENV-Rep. The molecular mechanisms of the antiviral action was analyzed using surface plasmon resonance, ultraviolet-visible spectral analysis and differential scanning calorimetry assays, as well as molecular docking analysis combined with site-directed mutagenesis. Results: In our in-house library of old drugs (~1000 compounds), a topical hemostatic and antiseptic 2-hydroxy-3,5-bis[(4-hydroxy-2-methyl-5-sulfophenyl)methyl]-4-methyl-benzene-sulfonic acid (policresulen) was found to be a potent inhibitor of DENV2 NS2B/NS3 protease with IC 50 of 0.48 μg/mL. Furthermore, policresulen inhibited DENV2 replication in BHK-21 cells with IC 50 of 4.99 μg/mL, whereas its IC 50 for cytotoxicity to BHK-21 cells was 459.45 μg/mL. Policresulen acted as a competitive inhibitor of the protease, and slightly affected the protease stability. Using biophysical technology-based assays and molecular docking analysis combined with sitedirected mutagenesis, we demonstrated that the residues Gln106 and Arg133 of DENV2 NS2B/NS3 protease directly interacted with policresulen via hydrogen bonding. Conclusion: Policresulen is a potent inhibitor of DENV2 NS2B/NS3 protease that inhibits DENV2 replication in BHK-21 cells. The binding mode of the protease and policresulen provides useful hints for designing new type of inhibitors against the protease.

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“…Any disruption in functional activities of NS2B-NS3pro complex inhibits viral replication [6]. Different compounds like, chemistry-derived benz[d]isothiazol-3(2H)-one derivatives (2- [2-Phenyl-1-(2-p-cyanophenyl-1,3,4-oxadiazol-5-yl)ethyl]-1,2- benzisothiazol-3(2H)-one (a), 2-[2-Phenyl-1-(2-p-fluorophenyl- 1,3,4-oxadiazol-5-yl)ethyl]-1,2-benzisothiazol-3(2H)-one (b), 2- [2-Phenyl-1-(2-p-methoxyphenyl-1,3,4-oxadiazol-5-yl)ethyl]- 1,2-benzisothiazol-3(2H)-one(c),2-[2-Phenyl-1-(2-phenyl-1,3,4- oxadiazol-5-yl)ethyl]-1,2-benzisothiazol-3(2H)-one (c), 2-[2- Phenyl-1-(2-p-chlorophenyl-1,3,4-oxadiazol-5-yl)ethyl]-1,2- benzisothiazol-3(2H)-one) (d) [7], SK-12 [8] and kalata B1 analogues have been reported as DENV NS2B-NS3 protease inhibitors [9]. But there is no effective drug available for the treatment of DENV infection yet [10].…”

Section: Introductionmentioning

confidence: 99%

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease

Qamar

Mumtaz²,

Ashfaq³

et al. 2014

Bioinformation

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Dengue virus NS2/NS3 protease because of its ability to cleave viral proteins is considered as an attractive target to screen antiviral agents. Medicinal plants contain a variety of phytochemicals that can be used as drug against different diseases and infections. Therefore, this study was designed to uncover possible phytochemical of different classes (Aromatic, Carbohydrates, Lignin, Saponins, Steroids, Tannins, Terpenoids, Xanthones) that could be used as inhibitors against the NS2B/NS3 protease of DENV. With the help of molecular docking, Garcinia phytochemicals found to be bound deeply inside the active site of DENV NS2B/NS3 protease among all tested phytochemicals and had interactions with catalytic triad (His51, Asp75, Ser135). Thus, it can be concluded from the study that these Gracinia phytochemicals could serve as important inhibitors to inhibit the viral replication inside the host cell. Further in-vitro investigations require confirming their efficacy.

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A small compound targeting the interaction between nonstructural proteins 2B and 3 inhibits dengue virus replication

Cited by 53 publications

References 20 publications

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction

Policresulen, a novel NS2B/NS3 protease inhibitor, effectively inhibits the replication of DENV2 virus in BHK-21 cells

Computer Aided Screening of Phytochemicals from Garcinia against the Dengue NS2B/NS3 Protease

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