scholarly journals Facile Synthesis and In Vitro Activity of N-Substituted 1,2-Benzisothiazol-3(2H)-ones against Dengue Virus NS2BNS3 Protease

Pathogens ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 464
Author(s):  
Farwa Batool ◽  
Muhammad Saeed ◽  
Hafiza Nosheen Saleem ◽  
Luisa Kirschner ◽  
Jochen Bodem
Keyword(s):  
Dengue Virus ◽  
Catalytic Triad ◽  
Virus Infectivity ◽  
Protease Inhibition ◽  
One Pot ◽  
Computational Docking ◽  
Virus Serotype ◽  
Ic50 Values ◽  
Pharmaceutical Properties

Several new N-substituted 1,2-benzisothiazol-3(2H)-ones (BITs) were synthesised through a facile synthetic route for testing their anti-dengue protease inhibition. Contrary to the conventional multistep synthesis, we achieved structurally diverse BITs with excellent yields using a two-step, one-pot reaction strategy. All the synthesised compounds were prescreened for drug-like properties using the online Swiss Absorption, Distribution, Metabolism and Elimination (SwissADME) model, indicating their favourable pharmaceutical properties. Thus, the synthesised BITs were tested for inhibitory activity against the recombinant dengue virus serotype-2 (DENV-2) NS2BNS3 protease. Dose–response experiments and computational docking analyses revealed that several BITs bind to the protease in the vicinity of the catalytic triad with IC50 values in the micromolar range. The DENV2 infection assay showed that two BITs, 2-(2-chlorophenyl)benzo[d]isothiazol-3(2H)-one and 2-(2,6-dichlorophenyl)benzo[d]isothiazol-3(2H)-one, could suppress DENV replication and virus infectivity. These results indicate the potential of BITs for developing new anti-dengue therapeutics.

scholarly journals Rational design of cyclic tetra and pentapeptides as therapeutic agents for dengue NS2B/NS3 protease using structure-based molecular docking (MOE and AutoDock 4.2)

2020 ◽  
Vol 11 (4) ◽  
pp. 5501-5510
Author(s):  
Nadeem Abdalsatar Abdalrazaq ◽  
Ezatul Ezleen Kamarulzaman
Keyword(s):  
Dengue Virus ◽  
Rational Design ◽  
3D Structure ◽  
Binding Pocket ◽  
Catalytic Triad ◽  
Computational Docking ◽  
Cyclic Tetrapeptides ◽  
Ns3 Protease ◽  
Autodock 4.2

Dengue virus infection is one of the health problems in tropical and subtropical countries. Although this disease is common, unfortunately, until now no licensed vaccine or relevant drugs available in the market. The first objective of this study is to design potent and selective peptidic inhibitors by studying the interactions between the designed peptides and the dengue NS2B/NS3 protease using computational docking technique and secondly to compare the quantitative and qualitative docking results using two independent docking programs (MOE and AutoDock 4.2). The proposed peptides were designed based on literature reviews and previous findings on the interaction between dengue NS2B/NS3 protease and reported peptides, thus, we designed ten cyclic tetrapeptides and twenty cyclic pentapeptides. The reported 3D structure of Wichapong and co-workers on the dengue NS2B/NS3 protease homology model was used in this study. The designed peptides were docked using MOE and AutoDock 4.2 softwares targeting dengue NS2B/NS3 protease. The results demonstrated that most of the proposed peptides were connected to the protease binding pocket and made interactions with the protease catalytic triad residues (His51, Asp75 and Ser135). Based on quantitative and qualitative docking results from the two docking programs, it showed that two cyclic tetrapeptides (1-C4 and 4-C4) and four cyclic pentapeptides (4-C5, 16-C5, 20-C5, and 6-C5) are the best potential inhibitors with the lowest free energy of binding and the high number of interactions with protease. In conclusion, the two independent docking programs could give almost the same results based on its quantitative and qualitative docking results. Thus, these potential peptides could serve as promising inhibitors for dengue virus. These findings will be further continued for the synthesis of these cyclic peptides and in vitro biological assays to confirm their activity.

scholarly journals Biological and Computational Studies for Dual Cholinesterases Inhibitory Effect of Zerumbone

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1215 ◽  
Author(s):  
Jayeong Hwang ◽  
Kumju Youn ◽  
Yeongseon Ji ◽  
Seonah Lee ◽  
Gyutae Lim ◽  
...  
Keyword(s):  
Docking Simulation ◽  
Inhibitory Effect ◽  
Potential Effect ◽  
Van Der Waals Interactions ◽  
Inhibitory Effects ◽  
Computational Docking ◽  
In Silico Docking ◽  
Ic50 Values ◽  
Physiological Benefits

Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) mediate the degradation of acetylcholine (ACh), a primary neurotransmitter in the brain. Cholinergic deficiency occurs during the progression of Alzheimer’s disease (AD), resulting in widespread cognitive dysfunction and decline. We evaluated the potential effect of a natural cholinesterase inhibitor, zerumbone, using in vitro target enzyme assays, as well as in silico docking and ADMET (absorption, distribution, metabolism, excretion, and toxicity) simulation. Zerumbone showed a predominant cholinesterase inhibitory property with IC50 values of 2.74 ± 0.48 µM and 4.12 ± 0.42 µM for AChE and BChE, respectively; however, the modes of inhibition were different. Computational docking simulation indicated that Van der Waals interactions between zerumbone and both the cholinesterases were the main forces responsible for its inhibitory effects. Furthermore, zerumbone showed the best physicochemical properties for both bioavailability and blood–brain barrier (BBB) permeability. Together, in the present study, zerumbone was clearly identified as a unique dual AChE and BChE inhibitor with high permeability across the BBB, suggesting a strong potential for its physiological benefits and/or pharmacological efficacy in the prevention of AD.

scholarly journals Drug of Action Cassia Alata Leaves Extract as Antiviral to Dengue Virus Serotype-2 in vitro

2020 ◽  
Vol 12 (4) ◽  
pp. 864-871
Author(s):  
Marissa Angelina ◽  
Muhammad Hanafi ◽  
Franciscus D Suyatna ◽  
Beti Ernawati Dewi
Keyword(s):  
Dengue Virus ◽  
Cassia Alata ◽  
Virus Serotype ◽  
Dengue Virus Serotype 2

scholarly journals Taraxacum officinale and Urtica dioica extracts inhibit dengue virus serotype 2 replication in vitro

2018 ◽  
Vol 18 (1) ◽  
Author(s):  
María R. Flores-Ocelotl ◽  
Nora H. Rosas-Murrieta ◽  
Diego A. Moreno ◽  
Verónica Vallejo-Ruiz ◽  
Julio Reyes-Leyva ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Taraxacum Officinale ◽  
Urtica Dioica ◽  
Virus Serotype ◽  
Dengue Virus Serotype 2

scholarly journals Mangifera foetida L. (Macang) Source of Potent Antiviral Activity of Against Dengue Virus Serotype 2 (Anti DENV2)

2021 ◽  
Vol 2049 (1) ◽  
pp. 012018
Author(s):  
Fitmawati ◽  
Maya Safitri ◽  
S.N. Kholifah ◽  
Emrizal ◽  
Rodesia Mustika Roza
Keyword(s):  
Dengue Virus ◽  
Vero Cells ◽  
Stem Bark ◽  
Selectivity Index ◽  
Assay Method ◽  
Bark Extract ◽  
Standard Curve ◽  
Virus Serotype ◽  
Stem Bark Extract

Abstract The new discovery about the potential of Mangifera foetida L. as an antiviral will help conservation efforts in nature while maintaining and increasing its biodiversity value. This study aims to characterize the in vitro potential of three varieties of M. foetida L. against the dengue virus. Dengue virus is infected in Vero cells, viral replication was measured using the Viral ToxGlo Assay method. The selectivity ability of Mangifera foetida L. stem bark extract to inhibit the dengue virus was seen from the Selectivity Index (SI) value. The standard curve between the concentration of the compound (μg/mL) and % cell viability was analyzed by linear regression using Microsoft Excel 2010 software. The results showed that the selectivity index (SI) value of M. foetida L stem bark extract of Limus, Manis and Batu varieties were 7.58, 6.82 and 16.43, respectively. It was concluded that the extract of Macang stem bark of the Limus, Manis and Batu varieties had the potential to be used as an antiviral for dengue.

scholarly journals Comparative Evaluation of Permissiveness to Dengue Virus Serotype 2 Infection in Primary Rodent Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jeanette Prada-Arismendy ◽  
Verónica Rincón ◽  
Jaime E. Castellanos
Keyword(s):  
Dengue Virus ◽  
Comparative Evaluation ◽  
Molecular Mechanisms ◽  
Rodent Species ◽  
Oligoadenylate Synthetase ◽  
Virus Serotype ◽  
Mouse Cells ◽  
Dengue Virus Serotype 2 ◽  
Denv2 Infection

Infection with dengue virus presents a broad clinical spectrum, which can range from asymptomatic cases to severe cases that are characterised by haemorrhagic syndrome and/or shock. The reason for such variability remains unknown. This work evaluated thein vitropermissiveness of mouse, rat, hamster and guinea pig macrophages to infection by dengue virus 2 (DENV2). The results established that macrophages derived from the BALB/c mouse strain showed higher permissiveness to DENV2 infection than macrophages from other rodent species, although all rodent species studied had the C820T mutation in the oligoadenylate synthetase 1b gene, indicating no relationship to the differentin vitrosusceptibilities of mouse cells at this locus. Other molecular mechanisms related to flavivirus susceptibility remain to be explored.

scholarly journals NS5 from Dengue Virus Serotype 2 Can Adopt a Conformation Analogous to That of Its Zika Virus and Japanese Encephalitis Virus Homologues

2019 ◽  
Vol 94 (1) ◽  
Author(s):  
Abbas El Sahili ◽  
Tingjin Sherryl Soh ◽  
Jonas Schiltz ◽  
Aïcha Gharbi-Ayachi ◽  
Cheah Chen Seh ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Japanese Encephalitis Virus ◽  
Japanese Encephalitis ◽  
Zika Virus ◽  
Nonstructural Protein ◽  
Vaccine Design ◽  
Encephalitis Virus ◽  
Virus Serotype ◽  
In Cells

ABSTRACT Flavivirus nonstructural protein 5 (NS5) contains an N-terminal methyltransferase (MTase) domain and a C-terminal polymerase (RNA-dependent RNA polymerase [RdRp]) domain fused through a 9-amino-acid linker. While the individual NS5 domains are structurally conserved, in the full-length protein, their relative orientations fall into two classes: the NS5 proteins from Japanese encephalitis virus (JEV) and Zika virus (ZIKV) adopt one conformation, while the NS5 protein from dengue virus serotype 3 (DENV3) adopts another. Here, we report a crystallographic structure of NS5 from DENV2 in a conformation similar to the extended one seen in JEV and ZIKV NS5 crystal structures. Replacement of the DENV2 NS5 linker with DENV1, DENV3, DENV4, JEV, and ZIKV NS5 linkers had modest or minimal effects on in vitro DENV2 MTase and RdRp activities. Heterotypic DENV NS5 linkers attenuated DENV2 replicon growth in cells, while the JEV and ZIKV NS5 linkers abolished replication. Thus, the JEV and ZIKV linkers likely hindered essential DENV2 NS5 interactions with other viral or host proteins within the virus replicative complex. Overall, this work sheds light on the dynamics of the multifunctional flavivirus NS5 protein and its interdomain linker. Targeting the NS5 linker is a possible strategy for producing attenuated flavivirus strains for vaccine design. IMPORTANCE Flaviviruses include important human pathogens, such as dengue virus and Zika virus. NS5 is a nonstructural protein essential for flavivirus RNA replication with dual MTase and RdRp enzyme activities and thus constitutes a major drug target. Insights into NS5 structure, dynamics, and evolution should inform the development of antiviral inhibitors and vaccine design. We found that NS5 from DENV2 can adopt a conformation resembling that of NS5 from JEV and ZIKV. Replacement of the DENV2 NS5 linker with the JEV and ZIKV NS5 linkers abolished DENV2 replication in cells, without significantly impacting in vitro DENV2 NS5 enzymatic activities. We propose that heterotypic flavivirus NS5 linkers impede DENV2 NS5 protein-protein interactions that are essential for virus replication.

scholarly journals Antiviral Activity of Isobutyl Gallate to Dengue Virus Serotype 2 In Vitro

2019 ◽  
Vol 251 ◽  
pp. 012018 ◽  
Author(s):  
B E Dewi ◽  
M Angelina ◽  
F Nuwwaaridya ◽  
H Desti ◽  
T M Sudiro
Keyword(s):  
Antiviral Activity ◽  
Dengue Virus ◽  
Virus Serotype ◽  
Dengue Virus Serotype 2

scholarly journals Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways

2020 ◽  
Vol 295 (33) ◽  
pp. 11388-11407 ◽  
Author(s):  
Anne Harbig ◽  
Marco Mernberger ◽  
Linda Bittel ◽  
Stephan Pleschka ◽  
Klaus Schughart ◽  
...  
Keyword(s):  
Influenza A ◽  
Transcriptome Profiling ◽  
Alveolar Epithelial Cells ◽  
Lower Airway ◽  
Mouse Lung ◽  
Influenza B ◽  
Virus Infectivity ◽  
Protease Inhibition ◽  
Deficient Mice

Cleavage of influenza virus hemagglutinin (HA) by host proteases is essential for virus infectivity. HA of most influenza A and B (IAV/IBV) viruses is cleaved at a monobasic motif by trypsin-like proteases. Previous studies have reported that transmembrane serine protease 2 (TMPRSS2) is essential for activation of H7N9 and H1N1pdm IAV in mice but that H3N2 IAV and IBV activation is independent of TMPRSS2 and carried out by as-yet-undetermined protease(s). Here, to identify additional H3 IAV- and IBV-activating proteases, we used RNA-Seq to investigate the protease repertoire of murine lower airway tissues, primary type II alveolar epithelial cells (AECIIs), and the mouse lung cell line MLE-15. Among 13 candidates identified, TMPRSS4, TMPRSS13, hepsin, and prostasin activated H3 and IBV HA in vitro. IBV activation and replication was reduced in AECIIs from Tmprss2/Tmprss4-deficient mice compared with WT or Tmprss2-deficient mice, indicating that murine TMPRSS4 is involved in IBV activation. Multicycle replication of H3N2 IAV and IBV in AECIIs of Tmprss2/Tmprss4-deficient mice varied in sensitivity to protease inhibitors, indicating that different, but overlapping, sets of murine proteases facilitate H3 and IBV HA cleavages. Interestingly, human hepsin and prostasin orthologs did not activate H3, but they did activate IBV HA in vitro. Our results indicate that TMPRSS4 is an IBV-activating protease in murine AECIIs and suggest that TMPRSS13, hepsin, and prostasin cleave H3 and IBV HA in mice. They further show that hepsin and prostasin orthologs might contribute to the differences observed in TMPRSS2-independent activation of H3 in murine and human airways.

scholarly journals Repurposing of Sitagliptin- Melittin Optimized Nanoformula against SARS-CoV-2; Antiviral Screening and Molecular Docking Studies

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 307
Author(s):  
Mohammed Al-Rabia ◽  
Nabil Alhakamy ◽  
Osama Ahmed ◽  
Khalid Eljaaly ◽  
Ahmed Aloafi ◽  
...  
Keyword(s):  
Particle Size ◽  
Molecular Docking ◽  
Zeta Potential ◽  
Docking Studies ◽  
Target Cells ◽  
Protease Inhibition ◽  
23 Factorial Design ◽  
Ic50 Values

The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. The objective of the current work was to evaluate the efficacy of the combined complex of Sitagliptin (SIT) with melittin (MEL) against SARS-CoV-2 virus. SIT-MEL nano-conjugates were optimized by a full three-factor bi-level (23) factorial design. In addition, SIT concentration (mM, X1), MEL concentration (mM, X2), and pH (X3) were selected as the critical factors. Particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for Fourier-transformed infrared (FTIR) was carried out. The optimized formula showed particle size and zeta potential values of 77.42 nm and 27.67 mV, respectively. When compared with SIT and MEL, the combination of SIT-MEL complex has shown anti-viral potential against isolate of SARS-CoV-2 with IC50 values of 8.439 μM with significant improvement (p < 0.001). In addition, the complex showed IC50 in vitro 3CL-protease inhibition with IC50 7.216 µM. Molecular docking has revealed that formula components have good predicted pocket accommodation of the SARS-CoV-2 3-CL protease. An optimized formulation of SIT-MEL could guarantee both enhanced delivery to the target cells and the enhanced cellular uptake with promising activities against SARS-CoV-2.

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