A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture

Raut, Rajendra; Beesetti, Hemalatha; Tyagi, Poornima; Khanna, Ira; Jain, Swatantra Kumar; Jeankumar, Variam Ullas; Yogeeswari, Perumal; Sriram, Dharmarajan; Swaminathan, Sathyamangalam

doi:10.1186/s12985-015-0248-x

Cited by 52 publications

(48 citation statements)

References 30 publications

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“…Therefore, disturbing the activity of dengue protease will contribute to blocking the viral replication in host cells. The NS2B/NS3 two-component protease of dengue virus is currently being investigated with the purpose of discovering small molecule inhibitors that are suitable as treatment options for the disease with the same name [42].…”

Section: Resultsmentioning

confidence: 99%

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Cabarcas-Montalvo

Maldonado-Rojas

Montes-Grajales

et al. 2016

European Journal of Medicinal Chemistry

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Background: Dengue disease is a global disease that has no effective treatment. The dengue virus (DENV) NS2B/NS3 protease complex is a target for designing specific antivirals due to its importance in viral replication and its high degree of conservation.Methods: NS2B/NS3 protease complex structural information was employed to find small molecules that are capable of inhibiting the activity of the enzyme complex. This inhibitory activity was probed with in vitro assays using a fluorescent substrate and the complex NS2B/NS3 obtained by recombinant DNA techniques, for testing the activity against dengue virus replication, HepG2 cells infected with dengue virus serotype 2 were used. Results: A total of 210,903 small molecules from PubChem were docked in silico to the NS2B/NS3 structure (PDB: 2FOM) to find molecules that were capable of inhibiting this protein complex. Five of the best 500 leading compounds, according to their affinity values (-11.6 and -13.5 kcal/mol), were purchased. The inhibitory protease activity on the recombinant protein and antiviral assays was tested. Conclusions: Chemicals CID54681617, CID54692801 and CID54715399 were strong inhibitors of NS2B/NS3, with IC 50 values (µM) and percentages of viral titer reductions of 19.9, 79.9%; 17.5, 69.8%; and 9.1, 73.9 %, respectively. Multivariate methods applied to the molecular descriptors showed two compounds that were structurally different from other DENV inhibitors. General significance: This discovery opens new possibilities for obtaining drug candidates against Dengue virus.

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Section: Resultsmentioning

confidence: 99%

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Cabarcas-Montalvo

Maldonado-Rojas

Montes-Grajales

et al. 2016

European Journal of Medicinal Chemistry

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“…Despite their nucleic acid and capsid differences, all of them possess a non-structural peptidase in their polyprotein, a serine protease. 34,35 In some viruses, the nucleophile serine of the serine protease is replaced by cysteine sulfhydryl as in picornavirus, yet sequence configuration remains homologous. 36 Viruses like dengue contain distinct chitin-binding domain (a carbohydratebinding domain) in this enzyme, 34 which might be indicative of their ability to invade their insect vectors.…”

Section: Virusmentioning

confidence: 99%

“…34,35 In some viruses, the nucleophile serine of the serine protease is replaced by cysteine sulfhydryl as in picornavirus, yet sequence configuration remains homologous. 36 Viruses like dengue contain distinct chitin-binding domain (a carbohydratebinding domain) in this enzyme, 34 which might be indicative of their ability to invade their insect vectors. Interaction of these serine proteases with host mannan binding lectins (MBL), the pattern recognition molecules have come forth.…”

Section: Virusmentioning

confidence: 99%

A critical review on serine protease: Key immune manipulator and pathology mediator

Patel

2017

Allergologia et Immunopathologia

107

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Proteolytic activity is fundamental to survival, so it is not surprising that all living organisms have proteases, especially seine protease. This enzyme in its numerous isoforms and homologues, constitutes the quintessential offence and defence factors, in the form of surface proteins, secreted molecules, gut digestive enzymes, venom in specialised glands or plant latex, among other manifestations. Occurring as trypsin, chymotrypsin, elastase, collagenase, thrombin, subtilisin etc., it mediates a diverse array of functions, including pathological roles as inflammatory, coagulatory to haemorrhagic. This review emphasizes that despite the superficial differences in mechanisms, most health issues, be they infectious, allergic, metabolic, or neural have a common conduit. This enzyme, in its various glycosylated forms leads to signal misinterpretations, wreaking havoc. However, organisms are endowed with serine protease inhibitors which might restrain this ubiquitous yet deleterious enzyme. Hence, serine proteases-driven pathogenesis and antagonising role of inhibitors is the focal point of this critical review.

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“…The BPA molecule is not a virus inhibitor and does not resemble lipids, which bind to the dengue surface . However, it contains hydrophobic parts similarly to structures reported as compounds that bind to dengue virus …”

Section: Figurementioning

confidence: 99%

Small‐Molecule Dengue Virus Co‐imprinting and Its Application as an Electrochemical Sensor

et al. 2017

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Polymers can be synthesized to recognize small molecules. This is achieved by introducing the target molecule during monomer self‐assembly, where they can be incorporated during cross‐linking polymerization. Following additional pre‐processing, the material obtained can then be applied as a sensing layer for these molecules in many applications. The sensitivity of the polymers depends on the “active sites” imprinted on the surface. Increasing the number of active sites on the polymers surface can be achieved by using nanoparticles as a platform to support and concentrate the molecules for imprinting. In this work, we report the first use of dengue virus as a supporting nanoparticle to make for a more effective polymer composite sensor for the detection of bisphenol A (BPA), which is an environmental contaminant. The dengue virus has a nanoparticle size of around 100 nm and its surface provides regions where lipids and hydrophobic compounds can bind, making it an ideal support. The mixing of BPA with dengue prior to monomer self‐assembly led to imprinted polymer surfaces with much higher density BPA binding sites and a limit of detection of 0.1 pm. We demonstrate that a BPA–dengue co‐imprinting polymer composite sensor shows a very high sensitivity for BPA, but with lower production costs and technical requirements than other comparable methods.

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A small molecule inhibitor of dengue virus type 2 protease inhibits the replication of all four dengue virus serotypes in cell culture

Cited by 52 publications

References 30 publications

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

Discovery of antiviral molecules for dengue: In silico search and biological evaluation

A critical review on serine protease: Key immune manipulator and pathology mediator

Small‐Molecule Dengue Virus Co‐imprinting and Its Application as an Electrochemical Sensor

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