Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors

Lima, Caroline Sprengel; Mottin, Melina; Assis, Letícia Ribeiro de; Mesquita, Nathalya Cristina de Moraes Roso; Sousa, Bruna Katiele de Paula; Coimbra, Laís D.; Bispo-dos-Santos, Karina; Zorn, Kimberley M.; Güido, Rafael Victório Carvalho; Ekins, Sean; Marques, Rafael Elias; Proença-Módena, José Luiz; Oliva, Glaucius; Andrade, Carolina Horta; Regasini, Luis Octávio

doi:10.1016/j.bioorg.2021.104719

Cited by 30 publications

(27 citation statements)

References 70 publications

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“…These efforts show the efficiency of integrating computational and experimental approaches to demonstrate how natural products can be used to discover new anti-ZIKV candidates. 49 This review has limitations. First, some studies were not included in the databases employed in this systematic review, which limits the number of potential molecules with inhibitory activity against ZIKV NS2B-NS3 pro that could be identified.…”

Section: Discussionmentioning

confidence: 99%

“…Part of the intermolecular interactions between the enzyme and compounds did not have a well-defined chemical bond. [41][42][43][44][45][46][48][49][50][51][52][53][54] In this context, 12 studies described the intermolecular interactions, such as hydrogen and hydrophobic bonds, involved in the activity of the compounds. 41,43,44,[46][47][48][49][50][51][52][53][54] Five compounds (Table 1, Entries 4, 5, 6, 7, and 17) showed the ability to interact with a region called 2B53 in NS3 (5/17, 29%), which contains essential amino acid residues to bind to NS2B.…”

Section: In Silico Studiesmentioning

confidence: 99%

“…[41][42][43][44][45][46][48][49][50][51][52][53][54] In this context, 12 studies described the intermolecular interactions, such as hydrogen and hydrophobic bonds, involved in the activity of the compounds. 41,43,44,[46][47][48][49][50][51][52][53][54] Five compounds (Table 1, Entries 4, 5, 6, 7, and 17) showed the ability to interact with a region called 2B53 in NS3 (5/17, 29%), which contains essential amino acid residues to bind to NS2B. Therefore, it is suggested that these compounds inhibit the NS3-NS2B pro interaction, which is crucial for the catalytic activity of this protease.…”

Section: In Silico Studiesmentioning

confidence: 99%

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NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

Nunes

Santos

Fonseca

et al. 2021

Journal of Medical Virology

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Zika virus (ZIKV) infections are associated with severe neurological complications and are a global public health concern. There are no approved vaccines or antiviral drugs to inhibit ZIKV replication. NS2B-NS3 protease (NS2B-NS3 pro), which is essential for viral replication, is a promising molecular target for anti-ZIKV drugs. We conducted a systematic review to identify compounds with promising effects against ZIKV; we discussed their pharmacodynamic and pharmacophoric characteristics. The online search, performed using the PubMed/MEDLINE and SCOPUS databases, yielded 56 articles; seven relevant studies that reported nine promising compounds with inhibitory activity against ZIKV NS2B-NS3 pro were selected. Of these, five (niclosamide, nitazoxanide, bromocriptine, temoporfin, and novobiocin) are currently available on the market and have been tested for off-label use against ZIKV. The 50% inhibitory concentration values of these compounds for the inhibition of NS2B-NS3 pro ranged at 0.38-21.6 µM; most compounds exhibited noncompetitive inhibition (66%). All compounds that could inhibit the NS2B-NS3 pro complex showed potent in vitro anti-ZIKV activity with a 50% effective concentration ranging 0.024-50 µM. The 50% cytotoxic concentration of the compounds assayed using A549, Vero, and WRL-69 cell lines ranged at 0.6-1388.02 µM and the selectivity index was 3.07-1698. This review summarizes the most promising antiviral agents against ZIKV that have inhibitory activity against viral proteases.

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Section: Discussionmentioning

confidence: 99%

Section: In Silico Studiesmentioning

confidence: 99%

Section: In Silico Studiesmentioning

confidence: 99%

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NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

Nunes

Santos

Fonseca

et al. 2021

Journal of Medical Virology

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“…Lim et al investigated several other polyphenol compounds which belong to flavonols, flavanols, flavones, and flavanones such as luteolin, chrysin, myricetin, ampelopsin, astragalin, rutin, icaritin, hesperidin, pyrogallol, pyrocatechol, caffeine, gallic acid against ZIKV NS2B-NS3 proteases, and observed the potential of these compounds in the inhibition of ZIKV replication ( Lim et al, 2017 ). In a molecular docking study, some flavonoids amentoflavone, fisetin, isorhamnetin, and theaflavin 3-gallate have shown potential inhibitory activity against ZIKV NS3-NS2B protease ( Bhargava et al, 2019 ; Zou et al, 2020 ; Eberle et al, 2021 ; Lima et al, 2021 ; Yadav et al, 2021 ). Roy et al based on in silico evidence indicated that several natural products such as myricetin, gossypol, naringenin, apigenin, luteolin, isorhamnetin, daidzein, resveratrol, and catechin inhibited Zika NS2B-NS3 via binding to a pocket on the active site and suppressed replication of ZIKV to be useful for the treatment of neurological diseases ( Roy et al, 2017 ; Cataneo et al, 2019 ; Gao et al, 2019 ).…”

Section: Zikvmentioning

confidence: 99%

Modulating Neurological Complications of Emerging Infectious Diseases: Mechanistic Approaches to Candidate Phytochemicals

et al. 2021

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Growing studies are revealing the critical manifestations of influenza, dengue virus (DENV) infection, Zika virus (ZIKV) disease, and Ebola virus disease (EVD) as emerging infectious diseases. However, their corresponding mechanisms of major complications headed for neuronal dysfunction are not entirely understood. From the mechanistic point of view, inflammatory/oxidative mediators are activated during emerging infectious diseases towards less cell migration, neurogenesis impairment, and neuronal death. Accordingly, the virus life cycle and associated enzymes, as well as host receptors, cytokine storm, and multiple signaling mediators, are the leading players of emerging infectious diseases. Consequently, chemokines, interleukins, interferons, carbohydrate molecules, toll-like receptors (TLRs), and tyrosine kinases are leading orchestrates of peripheral and central complications which are in near interconnections. Some of the resulting neuronal manifestations have attracted much attention, including inflammatory polyneuropathy, encephalopathy, meningitis, myelitis, stroke, Guillain-Barré syndrome (GBS), radiculomyelitis, meningoencephalitis, memory loss, headaches, cranial nerve abnormalities, tremor, and seizure. The complex pathophysiological mechanism behind the aforementioned complications urges the need for finding multi-target agents with higher efficacy and lower side effects. In recent decades, the natural kingdom has been highlighted as promising neuroprotective natural products in modulating several dysregulated signaling pathways/mediators. The present study provides neuronal manifestations of some emerging infectious diseases and underlying pathophysiological mechanisms. Besides, a mechanistic-based strategy is developed to introduce candidate natural products as promising multi-target agents in combating major dysregulated pathways towards neuroprotection in influenza, DENV infection, ZIKV disease, and EVD.

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“…Therefore, inhibiting the protease activity of ZIKV is a strategy to combat the virus [11,33,[47][48][49]. As the sequence of ZIKV protease exhibits high homology/identity with those of dengue and West Nile viral proteases, ZIKV protease inhibitors might show the broad activity against these viral proteases [50][51][52][53]. Indeed, three-dimensional structures of these viral proteases are very similar, which further demonstrates that it is possible to develop protease inhibitors with a broad antiviral spectrum.…”

Section: Introductionmentioning

confidence: 99%

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

Kang

2021

Biomedicines

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Zika virus (ZIKV)—a member of the Flaviviridae family—is an important human pathogen. Its genome encodes a polyprotein that can be further processed into structural and non-structural proteins. ZIKV protease is an important target for antiviral development due to its role in cleaving the polyprotein to release functional viral proteins. The viral protease is a two-component protein complex formed by NS2B and NS3. Structural studies using different approaches demonstrate that conformational changes exist in the protease. The structures and dynamics of this protease in the absence and presence of inhibitors were explored to provide insights into the inhibitor design. The dynamic nature of residues binding to the enzyme cleavage site might be important for the function of the protease. Due to the charges at the protease cleavage site, it is challenging to develop small-molecule compounds acting as substrate competitors. Developing small-molecule compounds to inhibit protease activity through an allosteric mechanism is a feasible strategy because conformational changes are observed in the protease. Herein, structures and dynamics of ZIKV protease are summarized. The conformational changes of ZIKV protease and other proteases in the same family are discussed. The progress in developing allosteric inhibitors is also described. Understanding the structures and dynamics of the proteases are important for designing potent inhibitors.

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Flavonoids from Pterogyne nitens as Zika virus NS2B-NS3 protease inhibitors

Cited by 30 publications

References 70 publications

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

NS2B‐NS3 protease inhibitors as promising compounds in the development of antivirals against Zika virus: A systematic review

Modulating Neurological Complications of Emerging Infectious Diseases: Mechanistic Approaches to Candidate Phytochemicals

Structure and Dynamics of Zika Virus Protease and Its Insights into Inhibitor Design

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