Interaction of small molecules with the SARS-CoV-2 papain-like protease: In silico studies and in vitro validation of protease activity inhibition using an enzymatic inhibition assay

Pitsillou, Eleni; Liang, Julia; Ververis, Katherine; Hung, Andrew; Karagiannis, Tom C.

doi:10.1016/j.jmgm.2021.107851

Cited by 33 publications

(35 citation statements)

References 109 publications

(113 reference statements)

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“…The in vitro study used a PLpro enzymatic inhibition assay to investigate the effect of epicatechin gallate (ECG) and epigallocatechin gallate (EGCG) on PLpro. While neither of the compounds showed high activity levels, the study suggests that ECG is slightly more effective at inhibiting PLpro in SARS-CoV-2, revealing essential differences in the structural-activity relationship when comparing anti-3CLpro to anti-PLpro mechanisms (Table 2) [128].…”

Section: Flavan-3-ols/flavanolsmentioning

confidence: 92%

“…Among these, 3CLpro was investigated against flavonols and flavones more than other subclasses of flavonoids. Tables 1 and 2 summarize the in vitro activities of various flavonoids against SARS-CoV-2 3CLpro, and PLpro reported in the literature, respectively [117][118][119][120][121][122][123][124][125][126][127][128].…”

Section: Antiviral Activity Of Flavonoids Against Sars-cov-2 Proteases (3clpro and Plpro)mentioning

confidence: 99%

“…Lastly, myricetin and rutin possess anti-SARS-CoV-2 PLpro activities, with the latter interacting with the naphthalene inhibitor binding pocket of the protease; however, both of their actions are relatively weak (Table 2) [117,128]. No flavanonols had anti-PLpro activities.…”

Section: Flavonols and Flavanonolsmentioning

confidence: 99%

“…Tannic acid, a polyphenol similar to a flavonoid, has the most substantial inhibitory effect on SARS-CoV-2 3CLpro among black garlic constituents with an IC50 of 9 µM using cell-free FRET assay [118]. Like tannic acid, the special polyphenol hypericin has extraordinary potential for its action against the PLpro [128]. Furthermore, other classes of flavonoids, such as anthocyanins contain compounds such as cyanidin-3-O-β-glucoside (Chrysanthemin), which display antiviral activity inhibiting PLpro by binding to the naphthalene inhibitor binding site, although showing limited inhibition (Table 2) [128].…”

Section: Othersmentioning

confidence: 99%

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Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

Kaul

Paul

Kumar

et al. 2021

IJMS

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The ongoing COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) became a globally leading public health concern over the past two years. Despite the development and administration of multiple vaccines, the mutation of newer strains and challenges to universal immunity has shifted the focus to the lack of efficacious drugs for therapeutic intervention for the disease. As with SARS-CoV, MERS-CoV, and other non-respiratory viruses, flavonoids present themselves as a promising therapeutic intervention given their success in silico, in vitro, in vivo, and more recently, in clinical studies. This review focuses on data from in vitro studies analyzing the effects of flavonoids on various key SARS-CoV-2 targets and presents an analysis of the structure-activity relationships for the same. From 27 primary papers, over 69 flavonoids were investigated for their activities against various SARS-CoV-2 targets, ranging from the promising 3C-like protease (3CLpro) to the less explored nucleocapsid (N) protein; the most promising were quercetin and myricetin derivatives, baicalein, baicalin, EGCG, and tannic acid. We further review promising in silico studies featuring activities of flavonoids against SARS-CoV-2 and list ongoing clinical studies involving the therapeutic potential of flavonoid-rich extracts in combination with synthetic drugs or other polyphenols and suggest prospects for the future of flavonoids against SARS-CoV-2.

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Section: Flavan-3-ols/flavanolsmentioning

confidence: 92%

Section: Antiviral Activity Of Flavonoids Against Sars-cov-2 Proteases (3clpro and Plpro)mentioning

confidence: 99%

Section: Flavonols and Flavanonolsmentioning

confidence: 99%

Section: Othersmentioning

confidence: 99%

See 2 more Smart Citations

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

Kaul

Paul

Kumar

et al. 2021

IJMS

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“…Here, our overall aim was to extend our previous studies to gain further insight into the potential antiviral activity of our lead compounds [ 20 , 29 , 43 ]. We performed all-atom molecular dynamics (MD) simulations (1 μs), PELE Monte Carlo simulations, and in vitro assays to further evaluate hypericin and cyanidin-3-O-glucoside as potential inhibitors of the SARS-CoV-2 M pro .…”

Section: Introductionmentioning

confidence: 99%

Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition

Liang

Pitsillou

Ververis

et al. 2022

Journal of Molecular Graphics and Modelling

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the ongoing COVID-19 pandemic. With some notable exceptions, safe and effective vaccines, which are now being widely distributed globally, have largely begun to stabilise the situation. However, emerging variants of concern and vaccine hesitancy are apparent obstacles to eradication. Therefore, the need for the development of potent antivirals is still of importance. In this context, the SARS-CoV-2 main protease (M pro ) is a critical target and numerous clinical trials, predominantly in the private domain, are currently in progress. Here, our aim was to extend our previous studies, with hypericin and cyanidin-3-O-glucoside, as potential inhibitors of the SARS-CoV-2 M pro . Firstly, we performed all-atom microsecond molecular dynamics simulations, which highlight the stability of the ligands in the M pro active site over the duration of the trajectories. We also invoked PELE Monte Carlo simulations which indicate that both hypericin and cyanidin-3-O-glucoside preferentially interact with the M pro active site and known allosteric sites. For further validation, we performed an in vitro enzymatic activity assay that demonstrated that hypericin and cyanidin-3-O-glucoside inhibit M pro activity in a dose-dependent manner at biologically relevant (μM) concentrations. However, both ligands are much less potent than the well-known covalent antiviral GC376, which was used as a positive control in our experiments. Nevertheless, the biologically relevant activity of hypericin and cyanidin-3-O-glucoside is encouraging. In particular, a synthetic version of hypericin has FDA orphan drug designation, which could simplify potential clinical evaluation in the context of COVID-19.

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Regeneration of Phytochemicals by Structure‐Driven Organization of Microbial Biosynthetic Steps

Guan

Han

et al. 2021

Angewandte Chemie

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Medicinal phytochemicals, such as artemisinin and taxol, have impacted the world, and hypericin might do so if its availability issue could be addressed. Hypericin is the hallmark component of Saint John's wort (Hypericum perforatum L.), an approved depression alleviator documented in the US, European, and British pharmacopoeias with its additional effectiveness against diverse cancers and viruses. However, the academia‐to‐industry transition of hypericin remain hampered by its low in planta abundance, unfeasible bulk chemical synthesis, and unclear biosynthetic mechanism. Here, we present a strategy consisting of the hypericin‐structure‐centered modification and reorganization of microbial biosynthetic steps in the repurposed cells that have been tamed to enable the designed consecutive reactions to afford hypericin (43.1 mg L−1), without acquiring its biosynthetic knowledge in native plants. The study provides a synthetic biology route to hypericin and establishes a platform for biosustainable access to medicinal phytochemicals.

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Interaction of small molecules with the SARS-CoV-2 papain-like protease: In silico studies and in vitro validation of protease activity inhibition using an enzymatic inhibition assay

Cited by 33 publications

References 109 publications

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

Promising Antiviral Activities of Natural Flavonoids against SARS-CoV-2 Targets: Systematic Review

Small molecule interactions with the SARS-CoV-2 main protease: In silico all-atom microsecond MD simulations, PELE Monte Carlo simulations, and determination of in vitro activity inhibition

Regeneration of Phytochemicals by Structure‐Driven Organization of Microbial Biosynthetic Steps

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